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Researchers at the National Human Genome Research Institute (NHGRI) are working with patients and families to better understand of how genes can cause or influence diseases and develop new and more effective diagnostics and treatments.

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Clinical studies give us a better understanding of how genes can cause or influence diseases. NHGRI researchers are working with patients, and with families with a history of inherited diseases, to learn more about the genetic components of common and rare disorders, and to develop new and more effective tests and treatments.

Deciding whether to participate in a clinical study is an important and personal process. Some reasons people choose to participate include:

  • Participants in clinical studies help current and future generations. Through these studies, researchers develop new diagnostic tests, more effective treatments, and better ways of managing diseases with genetic components.
  • Participants in studies are actively involved in understanding their disorder and current research.
  • Participants in some studies gain access to new tests and treatments before they are widely available.

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ADHD Genetic Research Study | NHGRI

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The following are conducted by NHGRI researchers. For eligibility requirements and contact information, visit the study on clinicaltrials.gov.

Last updated: January 12, 2023

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Yale Clinical Genetics is committed to providing excellent clinical care for adults and children in a setting that values compassion, collaboration, and respect for individuals and families.

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Backed by a team approach and a rich database of tissue samples and patient data, the Department of Clinical Genomics-Research is at the forefront of genomics-based research on everything from common forms of cancer to rare inherited disorders.

The Department of Clinical Genomics-Research at Mayo Clinic conducts research on a wide range of diseases and conditions that have a genetic basis, including common forms of cancer such as breast cancer, and rare and novel genetic disorders, such as lysosomal storage diseases.

The overarching goal of research within the Department of Clinical Genomics-Research is to further the scientific understanding of genetic-based diseases in order to help improve prevention, diagnosis and treatment for each patient.

Clinical genomics is truly a cross-specialty study. Genomics researchers work closely with their counterparts in many other research and clinical areas at Mayo Clinic, including the Department of Clinical Genomics , which includes experienced board-certified medical geneticists and certified genetic counselors who tailor care to each patient's needs.

Research being conducted in the Department of Clinical Genomics-Research also provides opportunities to participate in genetic research studies to improve overall patient care.

Research by our investigators — who are experts in medical genetics, neurology, pediatrics and other specialties — may eventually lead to better methods of screening, prevention and treatment for a wide array of genetic disorders. Our researchers are investigating breast cancer, ovarian cancer, colon cancer, congenital disorders of glycosylation, melanoma, lysosomal storage disease, neurofibromatosis, and rare or suspected genetic disorders.

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The research chair for the Department of Clinical Genomics-Research is physician-scientist David R. Deyle, M.D. , a medical geneticist at Mayo Clinic in Rochester, Minnesota, and an assistant professor of medical genetics at Mayo Clinic College of Medicine and Science. Dr. Deyle conducts research on improved methods of targeted genomic editing using viral vectors for the precise alteration of the human genome.

Working in a collaborative environment, we're striving to gain a better understanding of familial and congenital disorders. Contact us about research on breast cancer, ovarian cancer, colon cancer, lysosomal storage diseases, neurofibromatosis, schwannoma and other conditions.

Driven by genomics-focused research, we study breast cancer, ovarian cancer, colon cancer, congenital disorders of glycosylation, lysosomal storage disease, neurofibromatosis and schwannomas.

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clinical genetics research

Genomics study enrolls 100,000 participants

Colette Gallagher

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The Mayo Clinic Center for Individualized Medicine has achieved a milestone, finishing study recruitment after enrolling more than 100,000 participants in a pioneering genomics study nearly a year and a half ahead of schedule.

The  Tapestry DNA Sequencing Research Study  — a massive, decentralized clinical research study, aimed to complete exome sequencing of 100,000 Mayo patients and return the results to their electronic health records for three hereditary conditions: familial hypercholesterolemia — a form of high cholesterol; hereditary breast and ovarian cancer syndrome; and Lynch syndrome — a form of colorectal cancer.

The Tapestry study seeks to accelerate discoveries in individualized medicine to tailor prevention, diagnosis and treatment to a patient's unique genetic makeup. The study is poised to show that exome sequencing, when applied to a diverse general population, can proficiently identify people who carry genetic variants that put them at higher risk for a disease, enabling them to take preventive measures.

The project is a significant effort in scaling up the test for use in patient care, developing many first-time processes, including inviting approximately 1.3 million adults to participate.

The study has 114,000 consented participants. About 94,000 exomes have already been sequenced, with clinical results for 11 genes returned in the Plummer Chart as PDFs. Approximately 1.8% of the patients whose genomes have been sequenced carry a variant that increases their risk for the three hereditary conditions, and they have been offered genetic counseling and referrals for more follow-up when appropriate.

Soon, the patients' clinical results will be in the Plummer Chart as discrete data. This will be the first test to go live in the Mayo Clinic Clinical Practice Committee-sponsored Genomics Data Utilization Project. This project seeks to create discrete data in the health record, enabling ease of use in computing and searching capabilities for patient care.

Each participant's entire exome raw data are loaded into the Omics Data Platform in the Mayo Clinic Cloud, which includes a suite of tools for researchers. Already, 103 research teams across Mayo Clinic have requested use of these data to enhance their work in scientific discovery, translation and application to practice. Researchers interested in accessing these genomic data can contact the team a  [email protected] .

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Clinical Genetics Branch investigators conduct clinical, genetic, and epidemiologic studies of individuals at high risk of cancer in order to improve our understanding of cancer etiology and to advance clinical care.

Clinical Genetics Studies

CGB investigators conduct etiologic studies of individuals and families at increased risk of cancer to discover new cancer susceptibility or risk-modifying genes, to understand better the molecular pathogenesis of specific disorders, and to investigate possible genotype/phenotype relationships that will improve clinical management and aid in genetic counseling.

Familial Testicular Cancer Study  A study of the genetic causes of testicular cancer and the role of testicular microlithiasis (calcium deposits within testicular tissue) and risk of familial testicular cancer.

Inherited Bone Marrow Failure Syndromes The inherited bone marrow failure syndromes (IBMFS) are a group of rare genetic blood disorders. CGB investigators are leading a clinical study to better understand how cancers develop in persons with IBMFS.

Li-Fraumeni Syndrome Study   Li-Fraumeni Syndrome (LFS) is a rare, inherited disorder which leads to a higher risk of certain cancers. NCI has evaluated families with LFS since the syndrome was first recognized in 1969. DCEG is now expanding this research through a clinical study and participation in a multi-institutional collaboration.

Myotonic Dystrophy and Cancer Susceptibility Studies of cancer phenotype in the inherited nucleotide repeat neuromuscular disorder Myotonic Dystrophy (DM). 

Neurofibromatosis Type 1 Studies of Neurofibromatosis Type 1 to identify the additional genes that influence the wide variations in phenotype by applying the principles of translational medicine. 

Osteosarcoma Studies Genetic and descriptive studies of osteosarcoma, a primary bone cancer of adolescents and young adults.

Pleuropulmonary Blastoma  DICER1  Syndrome Study    An observational study of children with Pleuropulmonary blastoma (PPB), a rare tumor of the lung that may be part of an inherited cancer predisposition syndrome caused by changes in   DICER1 . 

Predictors of Outcomes after Allogeneic Hematopoietic Cell Transplantation  A study to identify predictive biomarkers of clinical outcomes in patients receiving allogeneic hematopoietic cell transplantation (HCT). 

Psychosocial Effects of Cancer Predisposition Syndromes  The Clinical Genetics Branch investigates and defines best practices of medical, psychosocial, and genetic counseling, as well as risk assessment and communication, to counsel and care for at-risk individuals and families.

Waldenström's Macroglobulinemia Study A study of the rare tumor, Waldenström's macroglobulinemia (WM), to determine what causes WM to sometimes develop in two or more family members.

Telomere Molecular Epidemiology Studies of nucleoprotein structures designed to protect the ends of chromosomes and are critical to chromosome stability. Research covers characterization of telomere length as a cancer risk factor and identification of genetic determinants of telomere length.

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CGB investigators in the Clinical Epidemiology Unit (CEU) study the molecular etiology of various cancers in order to identify at-risk individuals in the general population. They seek to translate our research findings into improved clinical practice and management.

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Ethical Issues in Contemporary Clinical Genetics

Genna braverman.

a Department of Internal Medicine, New York Presbyterian – Columbia University Medical Center, New York, NY

Zachary E. Shapiro

b The Hastings Center, Garrison, NY

Jonathan A. Bernstein

c Department of Pediatrics, Division of Medical Genetics, Stanford Children’s Health and Stanford University School of Medicine, Stanford, CA

As genetic sequencing capabilities become more powerful and costs decline, the reach of genomics is expanding beyond research laboratories to the wards, outpatient clinics, and, with the marketing of direct-to-consumer testing services, patients’ homes. Increasingly, patients receiving various diagnoses—from cancer to cardiomyopathy—can reasonably expect to have conversations with their providers about indications for genetic testing. In this dynamic context, a grasp of the ethical principles and history underlying clinical genetics will provide clinicians with the tools to guide their practice and help patients navigate complex medical-psychosocial terrain. This article provides an overview of the salient ethical concerns pertaining to clinical genetics. The subject is approached with an emphasis on clinical practice, but consideration is also given to research. The review is organized around the temporal and informational sequence of issues commonly arising during the course of pretesting, testing, and posttesting phases of patient care. Drawing from medical, legal, and historical perspectives, this review covers the following topics: (1) informed consent, (2) return of results, and (3) privacy and confidentiality, and intends to equip readers with an appropriate foundation to apply ethical principles to genetic testing paradigms with an understanding of the contextual landscape against which these situations occur.

In April 2017, the US Food and Drug Administration (FDA) announced that it would allow the genomics company 23andMe to market direct-to-consumer (DTC) genetic health risk tests for 10 medical conditions. 1 One year later, the FDA permitted the expansion of 23andMe’s reach by allowing the company to market testing for selected BRCA1/BRCA2 variants, which confer risk for breast and ovarian cancer. 2 Although the FDA maintains that such tests should not be used for diagnostic or treatment purposes and that consumers should consult health care professionals with questions or concerns about results, such decisions represent a sharp departure from its 2013 warning to the company to “immediately discontinue marketing.” 3 The agency’s reversal—and suggestion that other DTC technologies may enjoy expeditious approval—places it at odds with the current recommendations of the American College of Medical Genetics and Genomics (ACMG) regarding the assessment of an individual’s genetic risk. 4 In the setting of this discrepancy between professional society guidelines and market realities, the trend toward broader access to personal genetic information raises difficult questions for clinicians; chief among them: what are the specific ethical and legal obligations of physicians to their patients when genetic information is concerned?

The rise of DTC and genomic testing more broadly has occurred in a technological landscape undergoing tremendous flux. As genetic sequencing capabilities become more powerful and costs decline, the reach of genomics is expanding beyond research laboratories to the wards, outpatient clinics, and patients’ homes. Increasingly, patients receiving various common diagnoses—ranging from cancer to cardiomyopathy or autism—can reasonably expect to have conversations with their providers about indications for genetic testing, and as such, medical practitioners will face heightened need for genetics literacy.

As the universe of biomedical knowledge and technology rapidly expands, it is imperative that clinicians and researchers be equipped with sound ethical reasoning skills to guide their practice. To that end, this article is intended to provide an overview of salient issues in ethics as they pertain to clinical genetics. At the nexus of these fields lie several topics, to be reviewed in this article from medical, legal, and historical perspectives: (1) informed consent, (2) return of results, and (3) privacy and confidentiality. Furnished with this background, clinicians will be able to stay current as new developments shape the field, all the while guiding their patients through complex, dynamic medical and psychosocial terrains.

Informed Consent and Predictive Testing

Informed consent.

Informed consent is both an ethical and legal doctrine. Its formal origins can be traced to the 1947 Nuremberg Code that was drafted in the wake of the “Doctors’ Trial,” which scrutinized the human experimentation conducted under the Nazi regime. 5 The code sought to establish a set of conditions defining ethical human subjects research, and included voluntary consent as 1 of its 10 critical points. 5 In the United States, after revelations of egregious misconduct in the 40-year Tuskegee Syphilis Study, 6 the National Commission for the Protection of Human Services of Biomedical and Behavioral Research was established and in 1979 published its first set of principles and guidelines to protect the rights of research subjects. Known as the Belmont Report, the document outlines 3 basic tenets in the conduct of ethical research: respect for persons, beneficence, and justice. The Belmont Report elaborates practices to safeguard these principles: informed consent, risk/benefit assessments, and the selection of subjects, respectively. Informed consent in research is defined as the right of subjects to decide whether to participate in research, provided they are furnished with adequate information, possess full comprehension, and enjoy voluntariness of decision.

Postwar ethical violations in the research arena brought informed consent into sharp focus, but within the clinical landscape, the concept took root more slowly and less formally. The belief that provider and patient share in a decision-making partnership—requiring physician disclosure and patient consent—began to take hold in American medical practice through developments in case law during the 1950s and 1960s. 7 Clinically, the conditions of informed consent are similar to those outlined in the Belmont Report for research purposes: the patient must be apprised of all relevant information, have the capacity to reason soundly, and have the ability to exercise decision making freely. Only when disclosure, capacity, and voluntariness are present can informed consent be obtained. 8

A consideration of informed consent in clinical genetics practice begs the question: to what exactly are patients consenting when they agree to undergo genomic tests? Although patients may fully expect the return of primary results, they may not anticipate the trove of genetic data generated by testing and the fact that many detected variants have uncertain significance.

Although this information may be harmless, the possibility exists that the genetic testing could reveal embarrassing, stigmatizing, or deeply upsetting medical information. Furthermore, the test may reveal results with incomplete certainty, leading to misunderstanding and unnecessary concern for the recipient.

Predictive Testing of Minors

It is within this context that predictive testing of minors for genetic conditions has raised substantive ethical questions. Although minors are legally presumed to lack capacity—and thus are unable to grant consent—the legal threshold of majority is considered arbitrary by many ethicists, psychologists, and developmental specialists. 9 Nevertheless, under current law, clinicians are required to secure parental consent for medical treatment of patients younger than 18 years, with the exception of the “mature minor” common law precedents that apply to reproductive health care.

Predictive testing is defined as genetic testing of a presymptomatic individual. Members of the ethics and genetics communities broadly support predictive testing of adults for adult-onset diseases and minors for childhood-onset disorders for which medically beneficial interventions are available. 10 There exists an ethical gray zone, however, when it comes to predictive testing of minors for late-onset diseases or carrier status, particularly when there are no clear medical treatment or prevention options.

The arguments against predictive testing of minors were first proposed when clinical genetic testing was conducted on a small scale, primarily for adult-onset conditions with little or no available treatment. Such positions highlight the potential for psychological harm to the minor being tested, negative effects on the family as a whole, risk of social discrimination and restriction, as well as violation of future autonomy. 10 This reasoning supports the American Medical Association (AMA), ACMG, and American Academy of Pediatrics’ current recommendations to proceed with tests when the child is at risk for actionable conditions, to defer to parental discretion when the child is at risk for a pediatric-onset condition without effective intervention, and to delay testing until the age of majority when the child is at risk for a late-onset condition lacking effective prevention or treatment. 11 , 12

Arguments in favor of predictive testing of minors have gained traction in recent years. Supporters point to research emphasizing the psychological benefits of decreased uncertainty, positive effects on the family, an adolescent and family’s right to plan for the future, the prevention of harm that could result from not testing, and the principle of autonomy—both the right of parents to decide what is in their child’s best interest and the capacity of adolescents to make informed decisions about their health care. The authors of a recent review article on predictive testing of minors have noted that many of these arguments are testable, empiric claims, thus making further research to establish better guidelines and develop best practices essential. 10

Return of Results

As the costs of molecular diagnostic techniques fall and test efficiencies and capabilities rise, increased use of panel-based genetic testing and nontargeted whole-genome and exome sequencing will dramatically increase the frequency of incidental and secondary findings—that is, information not directly related to the original testing indication. The nomenclature in this field has evolved in recent years, with the term “incidental findings” covering both anticipatable and unanticipatable results not intentionally pursued at the outset of testing and “secondary findings” connoting those results that are not the primary target of testing but are nevertheless reasonably sought. As testing sensitivities increase and bundled testing becomes more cost-effective, the lines between these 2 categories are likely to blur further.

Clinical Considerations: The Case of Secondary Findings

The frequency of returnable secondary findings in study cohorts has been well documented. In a recent study of 1000 individuals’ exomes, researchers identified 239 unique, potentially pathogenic single nucleotide variants from among 114 genes associated with medically actionable conditions linked to 23 of the participants. Extrapolating these findings, the study concluded that 3.4% of patients of European descent and 1.2% of patients of African descent can reasonably expect to have highly penetrant pathogenic or likely pathogenic variants uncovered incidentally on exome sequencing. 13 The discrepancy along ancestral lines speaks to the relative dearth of research at present on populations not of European descent, a consideration for practitioners ordering genetic tests for particular patient groups. It should be noted that frequency estimates of incidental findings vary between studies. 14 , 15 Some of the variation relates to the inclusion or exclusion of individuals with a recognized family history of a Mendelian disorder, as well as the threshold used to assign pathogenicity to variants.

When physicians receive incidental or secondary findings in the course of testing, a question arises concerning what should be related to the patient. There is robust bioethical debate on the disclosure of such findings in clinical practice. There is consensus in the medical community that secondary findings with actionable clinical significance should be returned.

However, there is a spectrum of opinion about which conditions and variants meet these criteria, and the extent to which patient preference should be taken into account. Although studies have found widespread support among lay people for the return of clinically actionable secondary findings, 16 , 17 , 18 some patients can be expected to invoke their right not to know. 19 Such a situation pits autonomy and beneficence in direct opposition to each other. Supporters of disclosure advocate overriding a patient’s refusal of information when the incidental findings have confirmed clinical utility. 20 Yet the territory of “clinical utility” can be uncertain, particularly where material information is concerned. Providers may disagree whether findings such as carrier status, nonpaternity, consanguinity, or certain sex chromosome anomalies—which have the potential to impact both the patient and his or her family—meet the threshold of clinical utility.

Others advocate for a “right not to know” specific genetic information. Arguments against disclosure have ranged from respect for patient autonomy to the net harms of psychological impact, stigmatization, and overtreatment—particularly with regard to variants of unknown significance or results with low clinical utility. Countering this position is the argument that a lack of disclosure could impact later treatment decisions and thus reduce future autonomy.

A presidential commission and several physician body recommendations have encouraged disclosure, though they vary in their support for provider discretion. The President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, meeting in the 1970s and 1980s, used the example of nonpaternity as a starting point for discussion and advised that “full disclosure, combined with careful counseling that goes well beyond information-giving, would seem most likely to fulfill the principles of autonomy and beneficence. When circumstances preclude this, however, an approach that accurately provides information on the genetic risk, even when the individuals counseled are sometimes left with an incomplete understanding of the reasons, is generally preferable.” 21 Some 40 years later, the Presidential Commission for Bioethics adopted a markedly different stance when it issued its set of practice guidelines for clinicians, researchers, and DTC providers and specified that “clinicians should engage in shared decision making with patients about the scope of findings that will be communicated and the steps to be taken upon discovery of incidental findings.

Clinicians should respect a patient’s preference not to know about incidental or secondary findings to the extent consistent with the clinician’s fiduciary duty.” 22

In 2016, the ACMG updated its 2013 recommendations for the return of results for pathogenic mutations, which now includes 59 specified genes with disorders with high penetrance and actionable interventions. 23 Three years earlier, the group incited controversy when it recommended return of results for 56 enumerated genes despite patient preferences to the contrary, citing the fiduciary duty of clinicians and laboratory personnel to prevent harm regardless of patient wishes. At that time, the ACMG asserted that “this principle supersedes concerns about autonomy, just as it does in the reporting of incidental findings elsewhere in medical practice.” 24 , 25 This position met with considerable backlash, 26 , 27 , 28 , 29 and in 2015 the group published updated guidelines recommending that providers discuss “opt-out” provisions with patients during the consent process, thereby allowing the opportunity to refuse analysis of genes unrelated to the original indication for testing. 30

With regard to minors, the ACMG currently advocates reporting incidental findings regardless of the patient’s age, because pediatric sequencing may be the only opportunity for such results—which have relevance to the health of one or both parents—to come to light. In contrast, an older AMA guideline advised entering the secondary finding information into the medical record but deferring a discussion of the results until the child reaches majority or is making reproductive health decisions. 12 In the era of the Health Insurance Portability and Accountability Act and patient-accessible electronic medical records, the viewpoint expressed in the AMA guideline may not be implementable.

Research Considerations

In recent years, there has been a growing call for returning clinical trial results to study participants. Although the return of results is ethically and practically nuanced in the clinical sphere, the essential duty of a provider to secure the welfare of his or her patient provides a measure of clarity. In the research realm no such physician-patient relationship exists, and a researcher’s legal and ethical obligations to return results to subjects are murky.

At the heart of the distinction between research and clinical practice is a divergence of purpose. Clinical practice seeks to optimize health outcomes for an individual, whereas research pursues generalizable knowledge through hypothesis testing to optimize health outcomes for a population. Emerging from these differences are separate sets of legal obligations, ethical duties, and governing regulations covering clinicians and researchers, as well as separate sets of rights and protections owed to patients and subjects. Although researchers must protect subjects from harm, they have no duty to provide clinical benefit. Although laboratories conducting clinical genetic tests used in patient care must adhere to federally mandatory quality oversight and receive Clinical Laboratory Improvement Amendments (CLIA) certification, sites conducting genetic tests for research purposes alone are technically exempt, 31 though this exemption is controversial and contested when studies return individual research results. More recently, the FDA has made recommendations for next-generation sequencing testing in the research setting, particularly when there is return of results. 32 Furthermore, because many clinical trials take place overseas, the requirement to adhere to regulations and standards may become less clear.

The right to information critically distinguishes patients and research participants. In clinical practice, patients have an undisputed right to access their information under the Health Insurance Portability and Accountability Act. In research, participants are granted no such unrestricted right to information; in fact, institutional review boards retain the right to determine whether specific disclosures may harm subjects. Furthermore, subsequent researchers may want to use genetic data for future investigations, making it difficult to keep participants abreast of the various uses of their genetic data.

The obligation of researchers to return genetic testing results to subjects was at the heart of a 2002 Wisconsin case, Ande v. Rock , in which plaintiffs sued researchers, alleging wrongful birth due to the failure of physicians to discuss the risk of conceiving a child with genetic or congenital abnormalities. 33 At issue was a statewide, randomized controlled study involving newborn screening for cystic fibrosis (CF). The research was intended to assess whether early diagnosis of CF and subsequent nutritional intervention improved outcomes. Information on the research was included in a pamphlet that all parents received before their infant underwent mandatory newborn screening.

Under the research protocol, excess blood drawn during screening was provided to the investigators and tested for CF. The researchers notified families in the treatment arm when their child tested positive for CF and offered to place the infants on a nutritional support regimen; families in the control arm were not notified if their child tested positive for CF. When an expectant couple in the control group learned of their 2-year-old daughter’s CF diagnosis during clinical care unrelated to the study and their second child was subsequently diagnosed with CF at birth, they sued the researchers for medical malpractice. The Wisconsin Supreme Court ultimately held the researchers not liable. Reasoning that the provision of medical care is tightly bounded from a legal perspective by the requirement of a physician-patient relationship—a contractual agreement involving medical treatment—the court held that the return of results in the research setting failed to meet the bar for a physician-patient relationship.

Notwithstanding the outcome of this case, there are compelling ethical arguments for disclosing genetic findings to individual subjects. A number of consensus statements, guidelines, and committees have used clinical relevance and actionability as the benchmarks for returning individual results to study participants. 31 , 34 , 35 , 36 If results are to be returned, the possibility of disclosing such findings must be discussed during the informed consent phase, and the subject must have indicated a willingness to receive information. Furthermore, it is essential that planning for returning results be made during the development of clinical research protocols, because this will ensure that the practical mechanisms and funding are in place for this undertaking.

Although there are decreasing numbers of advocates for withholding individual research findings that are urgent and actionable, 37 a number of commentators have nevertheless broached concerns about returning results in the research setting. Such points tend to focus on the poorly understood nature of exploratory findings, 34 the unresolved question of whether individual research results in genetic studies are in fact subject to CLIA, 31 the resource burden of verifying results in CLIA-certified laboratories before return, 38 , 39 and the risk of therapeutic misconception, which occurs when a subject incorrectly believes that participation in a study will provide a clinical benefit. 40 , 41 Although these constraints are often a practical necessity, they may make it difficult for participants to grasp fully the information being provided to them, and may lead to more confusion and distress than warranted.

Further cost considerations and practical concerns weigh heavily. Much clinical research is undertaken in settings in which there is little long-term follow-up, and funding for continued monitoring is scarce. These concerns are compounded for research based in countries with less developed health care systems. In such situations, practical follow-up becomes more difficult, and even the most well-intentioned researchers may be unable to return results.

Last, an additional layer of complexity arises when physicians have both treatment and research relationships with patients. Given the broad ethical consensus, challenges to investigators moving forward will include working with institutional review boards to define returnable results and determining the means by which findings will be delivered to study participants.

Privacy and Confidentiality

Privacy and the threat to anonymity.

The right to privacy is tightly guarded in the American legal and cultural traditions, and Americans have come to expect informational privacy in health care delivery and health sciences research. 42 Informational privacy is the freedom from intrusive, public access to personal information, and within the health care sphere, confidentiality—the duty of entrusted third parties to safeguard an individual’s data—is a closely associated concept. 43 These values run up against the current direction of genetics research, which trends toward collaboration, data sharing, and large-scale research networks. Although data sharing in genomics research has enabled genome-wide association studies and research on rare conditions, such practices make the guarantee of subject anonymity harder to secure. 44

Threats to anonymity in the age of genomics have intensified with the growth of the genetic genealogy market. Genetic genealogy companies, such as 23andMe and Ancestry.com , offer to provide customers with information on distant patrilineal relatives by genotyping. In the past, these companies have focused on polymorphic short tandem repeats on the Y chromosome and have maintained massive databases linking Y-chromosome haplotypes to surnames. More recently, Y-chromosome single nucleotide polymorphism and autosomal single nucleotide polymorphism chip-based genotyping and next-generation sequencing have been used. 45 The privacy, security, and ultimate intention of these companies raise ethical quandaries about how private sensitive, genetic information will be and how accessible this data could be for both personal and commercial purposes.

Several cases have been reported of male adoptees and children of anonymous sperm donors using genetic genealogy services to identify the surname of their biological father; by genotyping themselves and searching the available databases, these individuals have been able to find paternal relatives and ultimately uncover the identity of the biological father. 46 Users of DTC genetic testing services have also experienced the incidental discovery of nonpaternity or previously unknown half-siblings. 47 , 48 As the Internet facilitates the aggregation of information and more research creates accessible large-scale genomic repositories, the potential for reidentification only promises to increase in the coming years. Given these recent cases, researchers have postulated that identifying individuals in sequencing projects would be possible by using similar methods. In a 2013 study, researchers were able to reidentify previously deidentified personal genomes using open-access, online resources; the researchers in this particular study had a 12% success rate in recovering the surnames of American white males through data triangulation. 49

The explosion in health information made possible by sequencing technologies has raised fears of discrimination against presymptomatic individuals found to be susceptible to genetic conditions. During the 1990s and early 2000s, these concerns were especially strong with respect to the insurance industry. The Genetic Information Non-Discrimination Act (GINA) was passed by the United States Congress in 2008 to counter widespread concerns about discrimination. Despite the legislation’s relative longevity and reach, many physicians are unaware of GINA or limited in their knowledge of its content. 50 The result of 13 years of debate in Congress, GINA prohibits health insurers and employers of 15 or more individuals from discriminating on the basis of genetic risk profile and bars these groups from requesting or requiring an individual to undergo genetic testing. Under GINA, an individual’s genetic information encompasses family history up to and including fourth-degree relatives. 51 Despite its expansion of protections for individuals at risk for genetic disorders, GINA has been criticized for a number of shortcomings. 52 Specifically, it does not cover life insurance, disability insurance, and long-term care insurance, and employers may still make conditional offers of employment contingent on employee disclosure of all health records, per the Americans with Disabilities Act. 53 Furthermore, the law applies only to individuals at risk for developing a disease with genetic basis, not to patients with known, existing disease. In addition to GINA, legal protections related to genetic discrimination and privacy are provided by laws in many, but not all, states.

Duty to Warn: The Limits of Confidentiality

Although physician-patient privilege forms a cornerstone of American medical practice, confidentiality in the doctor-patient relationship is not inviolable. A physician’s ethical and legal obligation to break confidentiality has been established by the duty to warn doctrine, which emerged from 2 rulings in the case of Tarasoff v. Regents of the University of California . The suit involved a graduate student, Prosenjit Poddar, who became obsessed with a fellow student, Tatiana Tarasoff, and told his psychologist that he was planning to kill her. Although the therapist contacted the police, Poddar was deemed rational and ultimately released; no direct warning was given to Tarasoff or her family. When Poddar killed Tarasoff some months later, Tarasoff’s family sued the university and several of its employees. The California Supreme Court found that therapists have a duty to protect identifiable victims of an intended violent crime by warning them directly, notifying the authorities, or taking any reasonable, necessary steps given the circumstances.

Although the Tarasoff rulings established that mental health professionals have a duty to protect third parties, the doctrine has expanded to cover medical providers as well. Such an expansion is evidenced in physician reporting of infectious diseases, impaired drivers, injuries from weapons, partner notification, intended violent crimes, child abuse, elder abuse, and intimate partner violence. The conditions warranting a Tarasoff invocation generally include a high likelihood of serious harm, a lack of less invasive means of warning those at risk, and an ability of the third party, once informed, to take measures to prevent harm.

Given the familial nature of genetic conditions, there arises an ethical and legal question when a physician learns the results of a patient’s genetic testing: what are the physician’s obligations to warn the patient’s family members of their genetic risk? Complicating the analogy to Tarasoff conditions are the uncertain realities of many genetic disorders—the harm may not be imminent because of the late onset of a condition, the harm may not be absolute due to incomplete penetrance or multifactorial inheritance, and there may be no actionable intervention to mitigate the harm.

Although several cases have addressed whether there is a duty to warn in the age of genomics, there is little consensus among judicial decisions. One of the earliest cases to take up the question was Pate v. Threlkel , decided by the Florida Supreme Court in 1995. 54 The plaintiff, Heidi Pate, sued her mother’s surgeon, Dr James Threlkel, 3 years after he treated Pate’s mother for medullary thyroid cancer, for which an autosomal-dominant familial form with high, but incomplete, penetrance exists. Pate alleged that Threlkel had a duty to warn Pate’s mother about the potential for a genetic basis to the cancer. After developing medullary thyroid cancer herself, Pate claimed she would have pursued preventative treatment had she originally been made aware of her genetic risk. 55 The court held that “physicians may owe a legal duty to the children of a patient if the children are identified beneficiaries of the prevailing standard of care” but that duty could be discharged by warning the patient directly. 54 Or, in other words, that the provider’s duty could be addressed by informing the patient that specific relatives were at risk and encouraging disclosure.

One year after Pate , the New Jersey Supreme Court reversed a lower court’s decision in Safer v. Estate of Pack . The suit centered on a case of familial adenomatous polyposis. Donna Safer, the adult daughter of Robert Batkin, sued the estate of Dr George Pack, Batkin’s physician, when she developed colon cancer. Pack had treated Batkin 40 years earlier for multiple polyposis, which at the time was known to have a heritable form. Safer alleged that Pack had a duty to warn his patient’s family members about their potential risk so that they could benefit from early screening and surveillance. The lower court ruled in favor of Pack’s estate on the grounds that physicians did not have a duty to warn someone with whom there was no physician-patient relationship and that genetic diseases were different from infectious diseases with respect to harm; this holding was then overturned by the superior court. In Pate, the Florida court had held that physicians could satisfy the duty to warn family members by counseling the affected patient, whereas in Safer , the court stipulated that physicians have a duty to warn family members directly.

Roughly 10 years later, the Minnesota Supreme Court in Molloy v. Meier took up the question of duty to warn a patient’s parents of recurrence risks. The case centered on the malpractice issue of failure to diagnose and the concomitant liability of failure to warn. In the early 1990s, Kimberly Molloy noticed her young daughter’s developmental delays and sought care from a pediatrician. The physician noted fragile X syndrome on the differential diagnosis but did not evaluate for it when ordering chromosomal testing, the results of which were reported as normal to the parents. The child was subsequently seen by a pediatric neurologist, who similarly failed to recommend testing for fragile X syndrome. When Molloy remarried and gave birth to a second child who was subsequently diagnosed with fragile X syndrome, Molloy sued her eldest daughter’s physicians for malpractice. 56 The Minnesota court held that a physician’s duty “regarding genetic testing and diagnosis extends beyond the patient to biological parents who foreseeably may be harmed by a breach of that duty,” 57 thus expanding the duty to warn to parents of childbearing age about recurrence risks.

Although states have disagreed on specific legal parameters of a clinician’s duty to warn family members of genetic testing results, professional societies have largely agreed that disclosure discretion should be left to the provider. 58 In 2009, the American Society of Human Genetics recommended that clinicians at a minimum inform patients about the familial implications of results, both before and after testing, and encourage disclosure to at-risk relatives. 59 Physicians have the discretion to inform family members when attempts at encouraging voluntary disclosure by the patient have failed, the risk of harm is likely, and the extent of harm is high, the at-risk individuals are identifiable, and there exists an actionable medical intervention.

With the advance of genetic and genomic technologies, the shortage of readily available genetic counselors, and the rise of at-home, DTC genetic testing, clinicians will increasingly be faced with the management and contextualization of their patients’ genetic information. This will put increased pressure on providers to understand the practical and ethical complexities of genetic testing. As the role of clinicians in this process is in steady flux, it is more important than ever that the medical community engages with and understands the promises, perils, and limitations of genetic tests. Indeed, for physicians to remain relevant and continue serving their patients, this knowledge and understanding will be essential.

We have endeavored to provide an overview of the ethical principles and history underlying clinical genetics essential for physicians navigating this constantly evolving landscape. As evidence-based ethics research is conducted and the gap is narrowed between technological capabilities and provider-targeted policies and recommendations, engagement with the ethics of genetic testing will allow clinicians to better serve their patients.

Acknowledgments

We acknowledge Kelly Ormond, MS, CGC, and Shonni Silverberg, MD, for their helpful comments and feedback.

Potential Competing Interests: The authors report no competing interests.

clinical genetics research

CRISPR Clinical Trials: A 2024 Update

It is a remarkable time for the development of CRISPR -based therapies. In late 2023, we saw the first-ever approval of CRISPR-based medicine: Casgevy, a cure for sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). The IGI has tracked the progress of CRISPR clinical trials since they first began, and this milestone has been anticipated for some time, but its speed is still noteworthy.

clinical genetics research

“Going from the lab to an approved CRISPR therapy in just 11 years is a truly remarkable achievement,” says IGI Founder Jennifer Doudna. “I am especially pleased that the first CRISPR therapy helps patients with sickle cell disease, a disease that has long been neglected by the medical establishment. This is a win for medicine and for health equity.”

With one CRISPR-based therapy across the finish line, we’re entering a new phase in the clinical development of genome editing in medicine.

clinical genetics research

“At this point, all hypotheticals, the words ‘potentially’ and ‘could’ or ‘in principle’ are gone,” says Fyodor Urnov, IGI’s Director of Technology & Translation . “CRISPR is curative. Two diseases down, 5,000 to go.” 

The enthusiasm in the field still has to face some significant real-world hurdles. Overall, the CRISPR medicine landscape has shifted significantly since our last update and Spring 2023. Market forces have reduced venture capital investment in biotechnology. Investors want to see returns, which means companies are hyper-focused on clinical trials and getting new products to market as quickly as possible to return on investment. Combined with the high price of clinical trials, financial pressure has led to layoffs in a number of CRISPR-focused companies and a narrowing of focus on their furthest developed products, rather than developing their pipeline of new treatments and expanding disease areas. This year, we see a trial in only one new disease area: autoimmunity. 

Innovative approaches to regulating CRISPR therapies and supporting clinical trials, especially for rare diseases, could help expand the pipeline. We’ll touch on this more at the end of the piece. First, we’ll cover the current clinical trials.

BLOOD DISORDERS

Image of a blue gene on a chromosome. The chromosome is unwound to expose nucleosomes for acetylation to ultimately expose DNA for transcription.

THE APPROVAL OF CASGEVY

On November 16, 2023, the UK’s Medicines and Healthcare Products Regulatory Agency approved Casgevy for the treatment of SCD and TDT in patients aged 12. The US Food and Drug Administration (FDA) followed with an approval for SCD on December 8, 2023. These were the first-ever approvals of a CRISPR-based therapy. Casgevy has since been approved in the US for the treatment of TDT, approved in the EU, and given conditional approval in Bahrain. A regulatory submission is in review with the Saudi FDA, with submission planned in Canada in 2024.

These approvals come following data from a phase 3 trial in both adults and children with severe SCD or TDT. CRISPR Therapeutics and Vertex have shared data from 17 patients with SCD and 27 patients with TDT: the results are dramatic and durable. 

25 of 27 individuals with TDT were no longer transfusion dependent following the treatment, some for longer than three years. The other two patients had significant reductions in transfusion frequency (80%, 96%). 16 of 17 SCD patients are free of the vaso-occlusive crises that characterize the illness following treatment. The other patient has been free of hospitalizations related to vaso-occlusive crises.

In all the patients who received Casgevy, increases in fetal hemoglobin occurred within the first few months and were maintained over time. Even without directly repairing the mutations that cause SCD or TDT, this treatment seems to be a functional cure for SCD and TDT. Hear from Victoria Gray , a participant with SCD who has experienced a remarkable recovery since undergoing treatment.

Much remains to be seen about access to Casgevy. The first issue is technological access: the treatment is challenging to manufacture and to deliver. Few locations in the United States or abroad have the technical ability and expertise to deliver the treatment.

The second set of challenges is financial access. Casgevy is priced at around $2 million per patient. Because the lifetime cost of care for individuals with SCD or TDT is so high, covering the treatment may be a sound strategy, particularly in countries with single-payer healthcare systems. In the United States, the incentive structure may prove to be more challenging. We will be keeping a keen eye on how insurance and Medicaid coverage play out in real life.

In addition to access and pricing issues, there are risk considerations. The chemotherapy required before administering the CRISPR treatment is tough on patients and carries the risk of serious side effects. Improving safety and patient experience, as well as reducing costs, are driving continued research on next-generation therapies.

Chart showing types of hemoglobin production over time

OTHER SCD AND TDT TRIALS

Editas Medicine is also conducting phase 1/2 trials for individuals with severe SCD and TDT, but using a CRISPR system with a Cas12a protein rather than the more famous Cas9 protein. Their approach, similar to Casgevy, is to create edits that turn on HbF. This is the first time Cas12 has been used in a clinical trial. So far, 17 participants have been treated. No serious adverse events have been reported, and the efficacy seems to be as strong as that of Casgevy: all of the SCD patients (11) show robust increases in fetal hemoglobin levels and have been free of vaso-occlusive events since they received the treatment (a minimum of five months). The 6 TDT patients have likewise had strong increases in hemoglobin that negate the need for transfusion. The treatment has been given orphan drug and RMAT designations by the FDA. Editas plans to treat more participants in the US and Canada, sharing more data in the summer of 2024.

Image of blue DNA helix with base pairs Adenine, Thymine, Cytosine and Guanine

A UC Consortium phase 1 trial is currently the only non-profit trial in the space, and the only one that aims to directly repair the SCD mutation. It has been delayed due to manufacturing challenges, but plans to begin enrolling in early 2025.

  • FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease
  • FDA approves first gene-editing treatment for human illness  

IMPROVING CRISPR TREATMENTS FOR SCD & TDT

CRISPR Therapeutics and Beam are both pursuing strategies for in vivo editing for SCD and TDT. Right now, all of the therapies are ex vivo: the cells are taken out of the body, edited and quality-controlled in a special lab, and then put back in the body after the patient undergoes intensive chemotherapy.  In vivo therapy would mean delivering the genome -editing medicine directly into the patient’s body, where the cells will be edited. 

Fyodor Urnov

Both companies are also investigating reducing the burden of chemotherapy conditioning by targeting the chemotherapy to specific cells with antibodies, ultimately allowing the use of lower doses. While CRISPR Therapeutics is farther along, all of this research is early-stage. But it’s something to keep an eye on — if successful,  these developments would reduce the burden on patients and in vivo editing could make treatment much more widely accessible.

“There is no doubt in my mind that in a decade we will move editing outside of the realm of the bone marrow transplantation unit and into a setting where the patient gets an IV injection. The path lies through the formidable obstacle of the risks of having something untoward happen,” says Urnov. “When you edit cells outside of the body, you test for quality control. Any in vivo editing regime for sickle cell disease, by definition, cannot involve this quality control step.”

CHRONIC BACTERIAL INFECTION

Urinary tract infections (UTIs) are a common infection that disproportionately affects women and causes over 8 million visits to health care providers every year. While most UTIs are easily treated with a short course of antibiotics, sometimes antibiotics are ineffective or the infection keeps recurring, leading to chronic UTIs. 

The treatment currently in clinical trials is a cocktail of three bacteriophages combined with CRISPR- Cas3 , designed to attack the genome of the three strains of E. coli responsible for about 95% of UTIs. The destruction of the genome kills the bacteria . 

Bacteriophages, or phages for short, are viruses that attack bacteria. In this treatment, in addition to the natural action of phages that kills bacteria, the bacteriophages are engineered to contain CRISPR-Cas3 in their genome. Lesser known than its famous cousin Cas9, Cas3 shreds DNA at the gene regions it is targeted to find. In this treatment, the CRISPR-Cas3 system is made to target the genomes of the targeted E. coli strains. Locus Biosciences delivered the treatment directly to the bladder by catheter.   

Locus Biosciences completed their US-based Phase 1b trial in February 2021. Locus’s trial was the first trial using a CRISPR-based therapy to treat infection. It is also the first trial to use the Cas3 protein. In press releases, Locus reported that results of the trial supported the safety and tolerability of the new therapy, with no drug-related adverse effects. No data have been published yet, but Locus says the initial results show a decrease in the level of E. coli in the bladder of participants given the CRISPR-based treatment. 

Locus began enrolling participants for a phase 2/3 trial in 2022, and announced dosing of the first participant in September 2022. They plan to enroll approximately 800 participants from the US and European Union. No clinical updates or interim data have been reported. 

Read more: 

  • Locus announces the dosing of the first patient in the phase 2/3 trial

PROTEIN-FOLDING DISEASE

the process of amyloidosis

This is the first clinical trial for a CRISPR-Cas9 therapy delivered in a lipid nanoparticle (LNP). LNPs have a tendency to accumulate in the liver. TTR is primarily made in the liver, so LNPs are a clever choice for getting the treatment to where it is needed. This is also the first trial to deliver genome-editing components systemically — that is, to the whole body rather than to one specific type of cell or tissue.

Diagram of lipid nanoparticles being administered by IV and travelling to the liver

The trial, sponsored by Intellia Therapeutics with sites in the EU, UK, and New Zealand, has two arms and dosed the first participants in late 2020. One arm is studying patients with neuropathy symptoms and the other is studying patients with with cardiomyopathy symptoms. Between the two arms, efficacy data has been reported on 62 participants at a range of doses. Even at the lowest treatment dose, there is a deep (>85%) reduction in the amount of toxic protein in the participants’ blood streams, with greater than 90% reduction for participants receiving the highest dose. All patients are showing sustained reduction in the TTR protein over time, including the patients for whom two years of findings have been reported. As TTR protein levels correlate with disease severity, researchers are very optimistic about participant outcomes. Some side effects have been observed, with mild infusion-related events particularly common. 7 of 65 participants experienced serious adverse effects. All patients remain in the study and a dose in the middle of the testing range has been selected to move forward for further testing.

Intellia has gotten FDA approval to move forward with a phase 3 study of NTLA-2001. This study will be double-blind and placebo-controlled, enrolling participants in the US and around the globe. These trials will be aimed at collecting sufficient efficacy data for treatment approval by the FDA and other regulatory agencies. 

  • CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis — Gillmore et al., New England Journal of Medicine
  • The latest data from Intellia

INFLAMMATORY DISEASE

In hereditary angioedema (HAE), an individual has severe attacks of inflammation, leading to swelling, often in the arms and legs, face, intestines, or airway. These attacks are painful and swelling of the airways can be life-threatening. Without treatment, attacks occur every 1–2 weeks, lasting 3–4 days each. HAE affects about 1 in every 100,000 people. 

The treatment that is currently in clinical trials uses CRISPR-Cas9 tools to reduce the amount of an inflammatory protein the body makes. As in the hATTR treatment, the aim isn’t to fix a gene, but to break a gene to stop a disease process. As in hATTR, the liver is the main site of protein production, and Intellia Therapeutics again used lipid nanoparticles to deliver the therapy. This is an in vivo, systemic treatment, administered intravenously in a single dose.

diagram shows how CRISPR could be used to treat hereditary angioedema

For HAE, researchers will use blood testing to see if the genome-editing components are successfully reducing the levels of proteins that cause inflammation as well as the number of inflammation attacks after treatment.

Early-stage trials are designed to test safety and find the appropriate dosage of the treatment. Intellia started dosing patients in New Zealand in 2020, testing a range of 3 doses on a total of 10 participants. Most participants have been free from attacks in the interval between treatment and their most recent follow-up — as long as 13 months. Four months after treatment, there was a reduction in the amount of inflammatory protein of an average of 64% in the lowest dose group and over 90% in the highest dose group. The treatment has been well tolerated at all dose levels, with no severe adverse events. Six participants discontinued use of their other HAE preventative treatments and remained free of attacks. These results are extremely encouraging, suggesting the one-time treatment may represent a functional cure for this type of HAE.

Participants from New Zealand, the US, and other locations have been dosed for the phase 2 portion of the trial, but no results have been released yet. Intellia plans to initiate a global phase 3 trial later this year.

The US FDA has given the treatment orphan drug and RMAT designations. In the EU, the treatment has been granted orphan drug and PRIME designations by the European Medical Agency. In the UK, the treatment has been granted an Innovation Passport, which is similar to the FDA’s Fast Track program.

  • Intellia’s press release with the latest clinical data
  • CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema

In CAR-T immunotherapy, researchers genetically engineer T cells to have a receptor that recognizes a patient’s cancer cells, telling the T cells to attack. The FDA approved CAR-T made with traditional gene therapy in 2017 and it’s proven to be an effective approach. With CRISPR, researchers are hoping to make it even more powerful.

clinical genetics research

Most CAR-T therapies are autologous : cells are taken from an individual patient, edited, multiplied, and then put back into the same patient. Autologous CAR-T and have long-lasting benefits for individuals with cancer . The treatment is completed with a single dose, but the process is expensive, time-consuming, and few facilities can do it. And sometimes the manufacturing process just doesn’t work, produces low potency cells, or individuals die of their disease while waiting for the manufacturing to be completed. 

A central focus for CRISPR researchers over the past several years has been making allogeneic CAR-T cells: cells from a healthy donor. These cells are edited to attack cancer cells and avoid being targeted by a recipient’s immune system, and then multiplied into huge batches which can be given to large numbers of recipients on demand. It has been hoped that allogeneic products would reduce cost, time until treatment, and provide consistently high-quality cells.

“Allogeneic CAR-T cells are incredibly challenging because you need to fight against cancer, but you also need to fight against the host immune system that can reject the CAR-T cells,” says Justin Eyquem, a cancer researcher based at UC San Francisco. “What we’ve been seeing over the past several years is that initially there is a high response rate to the allogeneic CAR-T therapy, but then the CAR-T cells are rejected and so we get frequent relapses. Using similar autologous cells, we have seen more prolonged anti-tumor responses.”

At this point, allogeneic CAR-T cells are largely being used as a bridge to stem cell transplant for leukemias and lymphomas, whereas autologous cells are a complete therapy on their own. So far, allogeneic CAR-T cells have so far not met the high hopes for them and investor excitement seems to have cooled, but researchers are continuing to seek new ways to make them more effective because they would offer significant advantages in cost and scalability. Still, companies are continuing to make improvements to their autologous CAR-T cells, including introducing additional edits to help them evade rejection by the patient’s immune system.

LEUKEMIAS & LYMPHOMAS

We previously reported that CRISPR Therapeutics was testing two kinds of allogeneic CRISPR-modified CAR-T cells in phase 1 clinical trials. One targeted CD70, a protein often present on the surface of cancerous cells in lymphomas and some solid tumors. The other treatment from CRISPR Therapeutics targets CD19, a protein often present on the surface of cancerous cells in leukemia and lymphoma. Read more about these types of cancers in 2022’ s clinical trials deep-dive . 

After sharing positive data from these trials, CRISPR Therapeutics decided to close them, opening instead phase 1/2 trials with the same targets, but featuring their next-generation technology. These changes include edits to two more genes, Renase-1 and TGFBR-2, that act as brakes on T cell anti-cancer activity. CRISPR Therapeutics reports that the next-generation treatments have better manufacturing profiles, producing more CAR-T cells per batch. The treatment targeting CD70 is being tested in individuals with kidney carcinomas and other solid tumors. The treatment targeting CD19 is being used in individuals with certain kinds of lymphomas and leukemias. 

Two other groups have had impressive results targeting CD19 for hard-to-treat, aggressive non-Hodgkin’s lymphomas. Caribou Biosciences is testing CAR-T cells that, in addition to targeting CD19, have a second genetic modification: knockout, i.e. genetic deactivation, of PD-1, a gene that cancer cells sometimes use to evade the immune system. The treatment was generally well-tolerated with an acceptable safety profile. In a US-based phase 1 trial of 16 participants, 15 responded to the treatment, with seven of 16 (44%) having a complete remission lasting six months or longer. 24 months is the longest complete remission maintained at the last reporting of data. The  FDA has granted their product RMAT , Fast Track , and orphan drug designations. At this time, Caribou is enrolling an additional 30 participants from the US, Australia, and Israel to help determine what dose to use in a phase 3 trial. They intend to go directly from phase 1 to a pivotal phase 3 trial, initiating the phase 3 trial by the end of 2024.

In 2023, Caribou initiated two more phase 1 allogeneic CAR-T trials. Their anti-BMCA CAR-T cells target multiple myeloma and their anti-CLL-1 CAR-T cells target acute myeloid leukemia. Both trials are US-based. No results have been reported yet.

A team out of the UK’s NIHR Great Ormond Street Hospital Biomedical Research Centre shared results from a small phase 1 trial using CD19-targeting cells in children with B cell leukemias, which achieved its safety aims. All together, this paints a promising picture for advances in treating blood cancers. 

  • More about CAR-T targeting CD19
  • More about effects of targeting CD70 in cutaneous lymphomas & the RMAT designation for this indication
  • Caribou’s release of phase 1 data  
  • Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL — Nature paper with the Bioray study
  • Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia — Science Translational Medicine paper on the study from the UK group

Allogeneic vs autologous

In 2022, the same Great Ormond Street group reported treating a teenager with CAR-T cells made with base editing, a kind of CRISPR-based editing that can make small changes to DNA without creating a double-stranded DNA break. This was the first use of base editing in a clinical trial. The teen, Alyssa, was treated with base-edited anti-CD7 CAR-T cells, made from allogeneic, or donor, cells. The treatment led to remission and serves as a bridge to a stem cell transplant, which can cure leukemia. In 2023, the group published a paper with results from two more teens with leukemia. One had successfully received the CAR-T treatment, gone into remission, and was awaiting transplant. The other responded to treatment but died from a fungal infection. 

Side effects of the treatment included significant inflammatory response in the form of cytokine release syndrome and opportunistic infections from immune system depression. While these side effects are significant, they must be weighed against outcomes without the treatment. Each of these teens had previously been treated but had relapsed. At that point, the prognosis was very poor and the alternative was palliative care. The group intends to treat a total of 10 patients in this phase 1 study and we expect to see more results shared in future.

Beam Therapeutics, a biotech company that uses base editing, reported dosing the first patient in their phase 1/2 of an anti-CD7 CAR-T treatment for T cell leukemia and lymphoma. Their cells also have edits to eliminate expression of three additional genes. Enrollment is ongoing and they expect to report data in the second half of 2024. 

  • Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia
  • Gene-editing ‘pencil’ saves two teenagers dying from cancer, putting their leukemia in remission

SOLID TUMOR CANCERS

We previously reported encouraging data from CRISPR Therapeutics’s trial using their allogeneic CD70-targeting CAR-T cells in individuals with solid tumors of the kidney. CRISPR Therapeutics has discontinued investigating this treatment, instead focusing on a next-generation version of the therapy with edits to additional genomic targets. We expect initial results from this trial to be reported later this year.

There are at least three other other phase 1 trials ongoing for solid cancers, including gastrointestinal, and epithelial-cell-derived cancers like breast and pancreatic cancers, but no results from these have been released yet.

  • CRISPR Therapeutics releases data on renal carcinoma treatment
  • PACT Pharma Reports Data From First Clinical Study Using CRISPR to Substitute a Gene in Patients’ Immune Cells to Treat Cancer
  • Non-viral precision T cell receptor replacement for personalized cell therapy — Nature paper with data from the PACT trial

CARDIOVASCULAR DISEASE

High levels of LDL cholesterol — so-called “bad cholesterol” — are a major risk factor for cardiovascular disease and premature death. Genetics play a role in cholesterol levels. Some individuals have mutations in the gene PCSK9 that leads to familial hypercholesterolemia: a heritable condition that causes dangerously high levels of cholesterol regardless of diet and exercise. 

In 2022, Verve Therapeutics began their trial for a subtype of familial hypercholesterolemia using a base editor delivered by lipid nanoparticle (LNP). Base editing is a form of CRISPR-based editing that can make small changes to DNA sequences without making a double-stranded break in the DNA. Double-stranded breaks create unique risks to cells, and base editing, when applicable, may be a safer alternative to conventional CRISPR-based editing. In this case, the editor is designed to make a single letter change in the PCSK9 gene. As in the case of hATTR and HAE, the liver is the major site of production of the protein in question. Lipid nanoparticles have a natural affinity for the liver, so LNP infusion is an obvious choice for delivery. Because the delivery is non-viral, the CRISPR components should only be present transiently, minimizing the risk of unwanted edits.

Overview from Verve Therapeutics of their approach to treating hypercholesterolemia

This phase 1 trial has been ongoing in New Zealand and the United Kingdom. The first participant received the treatment in July 2022, and a total of 10 participants have received the treatment. The first three participants were given a low dose and, once safety had been established, the next participants were given medium or high doses of the treatment. The two participants given the middle dose saw a 39% and 48% reduction in LDL cholesterol, respectively, while the participant given the highest dose saw a 55% reduction. These changes have been stable for six months, with monitoring ongoing. These are larger reductions than seen with statin medications, the conventional treatment for high LDL cholesterol. The levels of PCSK9 protein in the blood are also lower.

Some participants experienced mild adverse events, including flu-like symptoms. However, there were also three serious cardiovascular events. Two of these events, including the one that led to a death, were determined to be due to severe underlying coronary artery disease, while one was determined to potentially be related to treatment. 

The trial was originally intended to also enroll US participants, but was put on hold in the US due to an FDA request for additional data on the treatment itself and on risks of editing in germline cells (i.e., sperm and eggs). After providing more data, Verve got the green light to resume the trial in the US in October 2023. Verve is currently enrolling more participants for the medium and high dose cohorts. They plan to initiate a placebo-controlled phase 2 trial in 2025. 

  • First trial of ‘base editing’ in humans lowers cholesterol — but raises safety concerns
  • New Gene Editing Treatment Cuts Dangerous Cholesterol in Small Study
  • Latest data from Verve

In 2023, CRISPR Therapeutics initiated two phase 1 trials for additional targets for cardiovascular disease. Like the Verve trial, they rely on LNP delivery to the liver.

One trial targets angiopoietin-like 3 protein (ANGPTL3). Individuals who naturally have gene variants of ANGPTL3 that lead to reduced levels of the protein have reduced levels of lipids, or fats, and the blood and reduced risk of heart disease. The other trial targets lipoprotein(a) (Lp(a)). High levels of Lp(a) are also associated with heart disease. Unlike the PCSK9 trial, which targets a relatively rare gene variant associated with heart disease, these two trials are aimed at modifying the “wild type,” or, common version of a gene in individuals who may or may not have genetic risks for cardiovascular disease. If successful, these therapies would be aimed at much broader sections of the population. In fact, about one in five people in the United States and globally have elevated Lp(a). They have plans to target PCSK9 in the future as well. 

“Statin drugs like Lipitor were not initially trialed for prevention of cardiovascular disease in a general population,” says Urnov. “They were first trialed in people with severe cardiovascular disease due to genetic hyperlipidemia. Then they were trialed for people with significant, non-genetic cardiovascular disease. Finally, for prevention of cardiovascular disease. This is the model that Verve and CRISPR Therapeutics are following — first editing these genes in people with dangerous genetic variants. But we know from other research that editing these genes could prevent cardiovascular disease broadly. The real question is how quickly they move from genetic disease into prevention.”

Excision Bio aims to disable retroviruses by using CRISPR to make not one but two cuts in the DNA, excising a large part of the viral DNA from where it "hides" in the individual's own genome.

The phase 1 trial, which is sponsored by Excision Biotherapeutics, is the first to target HIV or any other chronic viral infection. The first participant was dosed in July 2022 and two more participants have since been dosed. As of October 2023, there were no reports of significant severe adverse effects. The company plans to to give a higher dose of the treatment to a second cohort, now that basic safety has been shown. This treatment has been given FDA Fast Track designation.

  • Excision announces dosing first participant

Researchers have long been interested in transplanting healthy pancreatic cells into individuals with type-1 diabetes (T1-D). While ongoing clinical trials in this area show that pancreatic cell transplantation can greatly benefit individuals with T1D, individuals who receive conventional pancreatic cell transplants must take drugs that suppress the immune system on an ongoing basis so that their body does not attack the transplanted cells. Immunosuppressant drugs can have serious side effects, including increased risk of dangerous infections and cancers. 

In 2022, we reported the start of a new clinical trial using pancreatic cells made from stem cells . CRISPR was used to edit the immune-related genes of these cells so that the patient’s immune system would not attack them. The cells were implanted into a patient’s body in a special pouch. Ideally, blood vessels would grow along the outside of the pouch, bringing the cells oxygen and vital nutrients from the blood, and taking up insulin from the cells. The aim was for patients to have healthy new pancreas cells to help control or even cure their T1D without having to take immunosuppressants. Stem-cell derived pancreatic cells also have a scalability advantage over conventional donor-matched or autologous transplants.  

This phase 1 trial was sponsored by CRISPR Therapeutics and ViaCyte and was the first use of CRISPR to treat an endocrine disease. However, shortly after the first patient was dosed in Spring 2022, ViaCyte was acquired by Vertex Pharmaceuticals and the trial was put on hold. The intellectual property rights have since been fully transferred to CRISPR Therapeutics and they intend to continue the phase 1 trial.

  • Sweet Spot: CRISPR Therapeutics, ViaCyte Dose First Patient with Cell Therapy for Type 1 Diabetes — Includes more detailed information on the approach
  • Vertex cuts ties to CRISPR Therapeutics’ type 1 diabetes stem cell therapy

AUTOIMMUNE DISEASE

Justin Eyquem poses for a portrait at UCSF's Parnassus Campus in San Francisco, CA on March 8th, 2022

Autoimmune diseases occur when the body’s immune system mistakenly targets the body’s own healthy cells and tissues. Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can cause tissue damage in almost any system of the body, most frequently affecting the skin, joints, kidneys, and heart. In severe cases, SLE can be disabling and cause life-shortening kidney disease and heart failure. SLE, like most autoimmune conditions, disproportionately affects women. In the US, the disease is more prevalent and more severe in women of color. Common treatments include hydroxychloroquine, steroids, and immunosuppressant medications, all of which can have serious side effects.

A small study in 2019 showed that conventional (non-gene-edited), autologous CAR-T cell therapy could put SLE into remission. Now, over 10 trials using conventional CAR-T to treat SLE are underway. CRISPR Therapeutics is initiating a trial treating patients with SLE with their next-generation CD19-targeting CAR-T cells. This will be the first application of CRISPR to the autoimmune space.

“People are super excited about this right now,” says Eyquem. “To treat cancer with CAR-T cells, the cells need to be able to persist in the body for a very long time, which remains a big challenge for allogeneic CAR-T cells. But preliminary clinical data suggest that it may not be true for treating autoimmune disorders. For autoimmunity, CAR-T could be used to quickly cause a complete depletion of immune cells called B cells. It seems like this can actually reset the patient’s immune system and have significant therapeutic benefit without needing the immunotherapy cells to persist for a long time. Right now, almost all CAR-T companies are opening an autoimmune disorder branch.”

Refer to the cancer section above for more information on CAR-T.

  • CAR T cell therapies raise hopes — and questions — for lupus and autoimmune disease

As the IGI has tracked CRISPR clinical trials each year, we’ve seen both an expansion in number and also in the disease areas being investigated, all on a remarkably short time scale. At the same time, there is growing understanding that novel regulatory approaches are needed to fully realize the therapeutic potential of CRISPR, especially for rare diseases. The traditional clinical trial pathway for the treatment that might be given to 10 patients a year can’t be the same as for treatment that will be given to 100,000. Europe, for example, has instituted the Hospital Exemption Rule, intended to benefit individuals with ultra-rare diseases. It allows an investigational genetic therapy to be developed at a hospital for use in a single patient. 

' style=

“The vision is that going from treating one condition to another will be much faster, cheaper, and more scalable than going back to square one,” says Urnov.

In 2022, the U.S. Congress passed legislation directing the FDA to create a platform technology designation. We hope to have more information on this legislation at our next update.

CLOSED TRIALS

Sickle cell disease.

  • As of 2022, two groups were taking the alternative approach of directly correcting the disease-causing gene variant for SCD to the more common, healthy variant. In 2022, Graphite Bio dosed one participant in their phase 1/2 trial. Their approach combines electroporation to get the CRISPR proteins into the cell and a viral vector to get a DNA “template” that the new gene variant can be copied off of into the cell. In early January 2023, Graphite shared that the first participant is experiencing prolonged low blood cell counts (pancytopenia) requiring ongoing blood transfusions and other treatments. Graphite reported the event to the FDA and is investigating what happened. Initially, they decided to voluntarily pause the trial, but recently announced that they are discontinuing development of their SCD treatment.
  • A phase 1/2 trial from Novartis and Intellia Therapeutics that takes the same approach as Casgevy had positive initial results, though the companies decided to discontinue in early 2023.
  • PACT Pharma did a US-based phase 1 trial for metastasized bladder, lung, head and neck, colorectal, ovarian, breast, and prostate cancers. Their approach was to analyze an individual tumor genome, and then use CRISPR to make an individual’s T cells target their specific tumor. Up to three different engineered T cells were given to each patient in their single-dose treatment. In November 2022, they shared data, stating that the gene-editing T cells preferentially infiltrated tumors, and led to tumor size reduction in one of 16 treated individuals.  They have since suspended the trial as a business decision. 
  • Presumed closed: Bioray Laboratories in conjunction with Zhejiang University have also shared positive results from a phase 1 trial in China for a similar product. In their study, 7/8 participants observed for about a year had a complete remission and durable responses without serious adverse events. 

Genetic Blindness

  • Leber congenital amaurosis (LCA), the most common cause of inherited childhood blindness. LCA10 was the target of the first in vivo CRISPR therapy trial, held in the US and sponsored by Editas Medicine. The first patient was dosed in March 2020 and dosing of small cohorts continued through July 2022. In November 2020, Editas revealed that only three out of 14 patients had “clinically meaningful” changes to their vision. Two of the three responders had mutations in both of their copies of the relevant gene, suggesting that this treatment may be most effective in this subset of the LCA10 population.This subset of an already rare condition is represented by only about 300 individuals in the United States. Because the patient population is so small, Editas has decided to stop clinical development of this treatment. 

Duchenne Muscular Dystrophy

  • Muscular dystrophies are a group of disorders that lead to muscle wasting and weakness. Duchenne Muscular Dystrophy (DMD) is the most severe form. Biotech nonprofit Cure Rare Disease (CRD) created a personalized treatment for an individual with DMD. The aim of the treatment was to increase production of an alternate form of the dystrophin protein. The participant was dosed in 2023 and died after the administration of the treatment. This is the first death associated with a CRISPR clinical trial. An autopsy of the participant showed that the cause of death was acute respiratory distress syndrome (ARDS), a severe inflammation of the lungs. ARDS was triggered by an immune response to the virus (AAV6) used to deliver the CRISPR components. The inflammation was caused by a reaction from the innate immune system. ARDS has not previously been documented as a response to genomic medicines delivered with this virus and the reaction could not have been predicted.

MORE INFORMATION ON CLINICAL TRIALS

If you or a loved one are interested in participating in a clinical trial, learn more about how US-based clinical trials work and where to find them on our Patients & Families page. Discuss all important medical decisions with your doctor. Keep in mind that clinical trials are the first tests of new medical treatments, so they are inherently risky and never guaranteed to be successful.

Thanks to Fyodor Urnov, Justin Eyquem, and Brian Shy for information and insights for this piece. 

Headshot of Hope Henderson

Hope Henderson holds a B.A. in Biology from Brown University and a Ph.D. in Molecular & Cell Biology from the University of California, Berkeley. She joined the IGI in 2019 to work in science communication. In addition to serving as IGI’s main writer, she plans content strategy and manages IGI’s social media, illustration, and translation. 

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Scientists develop a rapid gene-editing screen to find effects of cancer mutations

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Tumors can carry mutations in hundreds of different genes, and each of those genes may be mutated in different ways — some mutations simply replace one DNA nucleotide with another, while others insert or delete larger sections of DNA.

Until now, there has been no way to quickly and easily screen each of those mutations in their natural setting to see what role they may play in the development, progression, and treatment response of a tumor. Using a variant of CRISPR genome-editing known as prime editing, MIT researchers have now come up with a way to screen those mutations much more easily.

The researchers demonstrated their technique by screening cells with more than 1,000 different mutations of the tumor suppressor gene p53, all of which have been seen in cancer patients. This method, which is easier and faster than any existing approach, and edits the genome rather than introducing an artificial version of the mutant gene, revealed that some p53 mutations are more harmful than previously thought.

This technique could also be applied to many other cancer genes, the researchers say, and could eventually be used for precision medicine, to determine how an individual patient’s tumor will respond to a particular treatment.

“In one experiment, you can generate thousands of genotypes that are seen in cancer patients, and immediately test whether one or more of those genotypes are sensitive or resistant to any type of therapy that you’re interested in using,” says Francisco Sanchez-Rivera, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

MIT graduate student Samuel Gould is the lead author of the paper , which appears today in Nature Biotechnology .

Editing cells

The new technique builds on research that Sanchez-Rivera began 10 years ago as an MIT graduate student. At that time, working with Tyler Jacks, the David H. Koch Professor of Biology, and then-postdoc Thales Papagiannakopoulos, Sanchez-Rivera developed a way to use CRISPR genome-editing to introduce into mice genetic mutations linked to lung cancer.

In that study, the researchers showed that they could delete genes that are often lost in lung tumor cells, and the resulting tumors were similar to naturally arising tumors with those mutations. However, this technique did not allow for the creation of point mutations (substitutions of one nucleotide for another) or insertions.

“While some cancer patients have deletions in certain genes, the vast majority of mutations that cancer patients have in their tumors also include point mutations or small insertions,” Sanchez-Rivera says.

Since then, David Liu, a professor in the Harvard University Department of Chemistry and Chemical Biology and a core institute member of the Broad Institute, has developed new CRISPR-based genome editing technologies that can generate additional types of mutations more easily. With base editing, developed in 2016, researchers can engineer point mutations, but not all possible point mutations. In 2019, Liu, who is also an author of the Nature Biotechnology study, developed a technique called prime editing, which enables any kind of point mutation to be introduced, as well as insertions and deletions.

“Prime editing in theory solves one of the major challenges with earlier forms of CRISPR-based editing, which is that it allows you to engineer virtually any type of mutation,” Sanchez-Rivera says.

When they began working on this project, Sanchez-Rivera and Gould calculated that if performed successfully, prime editing could be used to generate more than 99 percent of all small mutations seen in cancer patients.

However, to achieve that, they needed to find a way to optimize the editing efficiency of the CRISPR-based system. The prime editing guide RNAs (pegRNAs) used to direct CRISPR enzymes to cut the genome in certain spots have varying levels of efficiency, which leads to “noise” in the data from pegRNAs that simply aren’t generating the correct target mutation. The MIT team devised a way to reduce that noise by using synthetic target sites to help them calculate how efficiently each guide RNA that they tested was working.

“We can design multiple prime-editing guide RNAs with different design properties, and then we get an empirical measurement of how efficient each of those pegRNAs is. It tells us what percentage of the time each pegRNA is actually introducing the correct edit,” Gould says.

Analyzing mutations

The researchers demonstrated their technique using p53, a gene that is mutated in more than half of all cancer patients. From a dataset that includes sequencing information from more than 40,000 patients, the researchers identified more than 1,000 different mutations that can occur in p53.

“We wanted to focus on p53 because it’s the most commonly mutated gene in human cancers, but only the most frequent variants in p53 have really been deeply studied. There are many variants in p53 that remain understudied,” Gould says.

Using their new method, the researchers introduced p53 mutations in human lung adenocarcinoma cells, then measured the survival rates of these cells, allowing them to determine each mutation’s effect on cell fitness.

Among their findings, they showed that some p53 mutations promoted cell growth more than had been previously thought. These mutations, which prevent the p53 protein from forming a tetramer — an assembly of four p53 proteins — had been studied before, using a technique that involves inserting artificial copies of a mutated p53 gene into a cell.

Those studies found that these mutations did not confer any survival advantage to cancer cells. However, when the MIT team introduced those same mutations using the new prime editing technique, they found that the mutation prevented the tetramer from forming, allowing the cells to survive. Based on the studies done using overexpression of artificial p53 DNA, those mutations would have been classified as benign, while the new work shows that under more natural circumstances, they are not.

“This is a case where you could only observe these variant-induced phenotypes if you're engineering the variants in their natural context and not with these more artificial systems,” Gould says. “This is just one example, but it speaks to a broader principle that we’re going to be able to access novel biology using these new genome-editing technologies.”

Because it is difficult to reactivate tumor suppressor genes, there are few drugs that target p53, but the researchers now plan to investigate mutations found in other cancer-linked genes, in hopes of discovering potential cancer therapies that could target those mutations. They also hope that the technique could one day enable personalized approaches to treating tumors.

“With the advent of sequencing technologies in the clinic, we'll be able to use this genetic information to tailor therapies for patients suffering from tumors that have a defined genetic makeup,” Sanchez-Rivera says. “This approach based on prime editing has the potential to change everything.”

The research was funded, in part, by the National Institute of General Medical Sciences, an MIT School of Science Fellowship in Cancer Research, a Howard Hughes Medical Institute Hanna Gray Fellowship, the V Foundation for Cancer Research, a National Cancer Institute Cancer Center Support Grant, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation Cancer Research Fund, Upstage Lung Cancer, and the Michael (1957) and Inara Erdei Cancer Research Fund, and the MIT Research Support Committee.

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Childhood Asthma in Urban Settings (CAUSE)

Childhood asthma in urban settings (cause) clinical studies.

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NIAID supports research to address the disproportionate public health burden of asthma in urban populations. NIAID funds the Childhood Asthma in Urban Settings (CAUSE) network to conduct research focused on understanding how the environment, allergens, and genetics interact with the body’s immune system to cause asthma and aggravate its symptoms. Launched in 2021, CAUSE builds upon research conducted through its predecessor program, the Inner-City Asthma Consortium (ICAC).

The following CAUSE clinical studies are currently recruiting or were recently completed. The links lead to full eligibility criteria, study site locations, and contact information:

Prevention of Asthma Exacerbations Using Dupilumab in Urban Children and Adolescents (PANDA) (NCT05347771) Prevention of asthma exacerbations is one of the primary goals of current asthma therapy. New treatment modalities such as biologics are playing an increasing role in asthma management as adjunctive therapy. PANDA is a multi-center, double-blind, placebo-controlled, randomized trial of the biologic dupilumab as adjunctive therapy for prevention of asthma exacerbations in urban children and adolescents with mostly allergic asthma.

Registry for Asthma Characterization and Recruitment 3 (RACR3) (NCT05272241) There is a need for people to take part in research studies to learn more about diseases and how to treat them. RACR3 will create a database of participants of all ages with asthma and nasal allergies, or risk factors for these conditions, who are potentially eligible for future CAUSE trials.

Cockroach Immunotherapy in Children and Adolescents (CRITICAL) (NCT03541187) Scientific evidence has shown that, over the past two decades, the combination of cockroach allergy and cockroach exposure is one of the most important factors contributing to the dramatic increase in asthma morbidity seen in disadvantaged urban children with asthma. The primary objective of this study that is now complete was to determine if asthma severity can be improved by cockroach subcutaneous immunotherapy treatment.

Read more about the  NIAID role in asthma research .

Visit the NIH website to learn about the  importance of children in clinical studies .

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  • Published: 06 March 2024

Genetics of chronic respiratory disease

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  • Catherine John 3 , 4 ,
  • Jing Chen   ORCID: orcid.org/0000-0003-1287-1930 3 &
  • Ian P. Hall   ORCID: orcid.org/0000-0001-9933-3216 1 , 2  

Nature Reviews Genetics ( 2024 ) Cite this article

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  • Developmental biology
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  • Genetic variation

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases are frequently occurring disorders with a polygenic basis that account for a large global burden of morbidity and mortality. Recent large-scale genetic epidemiology studies have identified associations between genetic variation and individual respiratory diseases and linked specific genetic variants to quantitative traits related to lung function. These associations have improved our understanding of the genetic basis and mechanisms underlying common lung diseases. Moreover, examining the overlap between genetic associations of different respiratory conditions, along with evidence for gene–environment interactions, has yielded additional biological insights into affected molecular pathways. This genetic information could inform the assessment of respiratory disease risk and contribute to stratified treatment approaches.

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    It is a remarkable time for the development of CRISPR-based therapies.In late 2023, we saw the first-ever approval of CRISPR-based medicine: Casgevy, a cure for sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). The IGI has tracked the progress of CRISPR clinical trials since they first began, and this milestone has been anticipated for some time, but its speed is ...

  24. Overview

    The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease. • Genome rearrangements and disease. • Epigenetics and disease. • The translation of genotype to phenotype.

  25. Scientists develop a rapid gene-editing screen to find effects of

    Caption: Using a variant of CRISPR genome-editing known as prime editing, MIT researchers have developed a method to screen cancer-associated genetic mutations much more easily and quickly than any existing approach. This illustration, by Samuel Gould's brother Owen Gould, is an artistic interpretation of the research and the idea of "rewriting the genome," explains Samuel.

  26. The road ahead in genetics and genomics

    In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics.

  27. Research shows that Black individuals with a genetic mutation in the

    The All of Us Research Program is an NIH-funded program that aims to recruit a diverse group of individuals from across the United States and promote precision medicine research by providing researchers with access to genetic and phenotypic data. Naman Shetty, M.D. (left), and Pankaj Arora, M.D. (right), are UAB researchers involved in the study.

  28. The power of representation: Statistical analysis of diversity in US

    For example, hiring research specialists from a community to translate study materials increases the chances of using appropriate, non-stigmatizing language. 44 CBPR, though underutilized, has successfully led to increased participation of non-White populations in genetic research and could be a useful approach for increasing recruitment across ...

  29. Childhood Asthma in Urban Settings (CAUSE) Clinical Studies

    NIAID supports research to address the disproportionate public health burden of asthma in urban populations. NIAID funds the Childhood Asthma in Urban Settings (CAUSE) network to conduct research focused on understanding how the environment, allergens, and genetics interact with the body's immune system to cause asthma and aggravate its symptoms.

  30. Genetics of chronic respiratory disease

    This research has contributed to the development of several biologic therapies coming to the clinic that target ... Hardin, M. et al. The clinical and genetic features of COPD-asthma overlap ...