Recombinant DNA Advisory Committee Research Articles

Key priorities for cell & gene therapy manufacturing evolution in 2023 & beyond

David McCall, Commissioning Editor,BioInsights, spoke to David DiGiusto, Senior Vice President, Stem Cells and Regenerative Medicine, National ResilienceDavid DiGiusto is the Senior Vice President for Stem Cells and Regenerative Medicine at National Resilience. He has over 28 years of experience in the scientific, clinical and regulatory aspects of cells as therapeutic agents including the isolation, characterization and genetic modification of hematopoietic stem cells, T cells and regenerative medicine products for clinical applications. He has been instrumental in the creation of seven GMP compliant biologics manufacturing facilities and associated quality systems, production and QC testing programs. Under his direction, plasmid DNA, CAR-T cells, regulatory T cells, engineered stem cell grafts and gene modified hematopoietic stem cell products have been manufactured and released for use in Phase 1/2 clinical trials. David is a major contributor to first in human studies for Cancer and HIV Gene Therapy and has developed methods for assessing ex vivo stem cell manipulations using in vitro and in vivo models. David is a former member of the NIH recombinant DNA advisory committee (RAC) and an independent consultant to the Biotechnology industry.

Governing Heritable Human Genome Editing: A Textual History and a Proposal for the Future.

Heritable human genome editing (HHGE) has become a topic of intense public interest, especially since 2015. In the early 1980s, a related topic—human genetic engineering—was the subject of sustained public discussion. There was particular concern about germline genetic intervention. During the 1980s debate, an advisory committee to the Director of the National Institutes of Health (NIH)—the Recombinant DNA Advisory Committee (RAC)—agreed to provide initial public review of proposals for deliberate introduction of DNA into human beings. In 1984 and 1985, the RAC developed guidelines for research involving DNA transfer into patients. The committee also commented on the possibility of deliberately altering the human germline. We track the textual changes over time in the RAC's response to the possibility of germline genetic intervention in humans. In 2019, the NIH RAC was abolished. New techniques for genome editing, including CRISPR-based techniques, make both somatic and germline alterations much more feasible. These novel capabilities have again raised questions about oversight. We propose the creation of a new structure for the public oversight of proposals to perform HHGE. In parallel with a technical review by a regulatory agency, such proposals should also be publicly evaluated by a presidentially appointed Bioethics Advisory Commission.

Pre-clinical development of multiplex-CRISPR-edited cell and gene therapy products

Background & Aim Data from a recent clinical trial at the University of Pennsylvania (UPenn) demonstrate the safety of NYCE T cells, which are autologous, patient-derived T cells transduced with lentivirus to express NY-ESO-1 T cell receptor and multiplex-edited with CRISPR/Cas9 at three distinct genes. This pilot study was the first in the United States (US) to administer CRISPR-edited cells to a patient. The preclinical approach and data in support of this trial was reviewed by the National Institutes of Health Recombinant DNA Advisory Committee (NIH RAC) in 2016, followed by the acceptance of an Investigational New Drug (IND) application by the US Food and Drug Administration. The aim of this abstract is to introduce the experience of an academic institution in the development of a preclinical program to support submission of an IND application for a cell therapy product with CRISPR-mediated gene editing. Non-clinical assays, data, and FDA feedback on IND submissions for CRISPR-edited gene products at the Center for Cellular Immunotherapies at UPenn will be presented. Methods, Results & Conclusion The preclinical program for the US IND application for UPenn's NYCE T cell therapy product paired conventional T cell phenotyping assays and novel genome editing evaluations. A comprehensive IND application for NYCE T cells was packaged out of inter-disciplinary collaborations to evaluate safety and potency of CRISPR-edited, antigen-directed T cells as well as fulfill NIH RAC and FDA requests. Results of these analyses will be presented. Execution of the NYCE T cell IND led to preclinical strategies toward applying CRISPR-editing to improve upon other T cell therapies, such as chimeric antigen receptor (CAR) T cells. As such, UPenn is developing an “off-the-shelf” CAR T cell product with healthy donor T cells utilizing CRISPR-mediated knock-down of genes encoding endogenous allo-reactive proteins. The parallels between the NYCE and the off-the-shelf CAR T cell non-clinical development pathways will be discussed.

NIH Guidelines April 2019.

Following the required review period initiated in August 2018, the Department of Health and Human Services, National Institutes of Health (NIH), published the final changes to the Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) in April 2019. This amendment focused on the review, registration, and reporting requirements for human gene transfer studies. In addition, the Recombinant DNA Advisory Committee (RAC) was renamed the Novel and Exceptional Technology and Research Advisory Committee (NeXTRAC) to serve as an advisory body on emerging technologies.

Diversity, Pathogenicity and Pandemic Potential of Henipavirus : an Interview With Benhur Lee

Biography Dr Benhur Lee is a Professor of Microbiology at the Icahn School of Medicine at Mount Sinai (ISMMS, NY, USA). He obtained his MD from Yale University School of Medicine (1995) and completed his clinical/postdoctoral training at the University of Pennsylvania (1995–2001). He was a Professor in the Department of Microbiology, Immunology & Molecular Genetics at the David Geffen School of Medicine at UCLA (2001–2013). Dr Lee is an appointed member of the NIH Novel and Exceptional Technology and Research Advisory Committee (NExTRAC), formerly known as the recombinant DNA Advisory committee (RAC). He is also on the International Committee on Taxonomy of Viruses (ICTV, paramyxovirus study group). Dr Lee has a special interest in emerging RNA viruses and HIV with a focus on molecular viral-host interactions that govern virus entry and budding.

LeRoy Walters’s Legacy of Bioethics in Genetics and Biotechnology Policy

LeRoy Walters was at the center of public debate about emerging biological technologies, even as "biotechnology" began to take root. He chaired advisory panels on human gene therapy, the human genome project, and patenting DNA for the congressional Office of Technology Assessment. He chaired the subcommittee on Human Gene Therapy for NIH's Recombinant DNA Advisory Committee. He was also a regular advisor to Congress, the executive branch, and academics concerned about policy governing emerging biotechnologies. In large part due to Prof. Walters, the Kennedy Institute of Ethics was one of the primary sources of talent in bioethics, including staff who populated policy and science agencies dealing with reproductive and genetic technologies, such as NIH and OTA. His legacy lies not only in his writings, but in those people, documents, and discussions that guided biotechnology policy in the United States for three decades.

In Honor of LeRoy Walters: Introduction from the Editors.

In Honor of LeRoy Walters: Introduction from the Editors Eric M. Meslin (bio), Eric T. Juengst (bio), and Carol Mason Spicer (bio) Since the birth of bioethics, a persistent refrain has been that advances in science, technology, and health are occurring so quickly that they threaten to outpace society’s ability to understand and react to them. Genomics, big data, and synthetic biology preoccupy current scholarly and policy debates, just as organ transplantation, in vitro fertilization, human subjects research, and gene therapy did over the past forty years. But the history of bioethics is more than the topics it has addressed. It is also the story of the people whose voices shaped its debates and built society’s capacity to manage the escalating pace of technological change. LeRoy Walters is one of those contributors who made a difference. He is part of an original community of scholars and intellectuals who were involved in these issues from the earliest days of bioethics. Now an Emeritus Faculty at the Kennedy Institute of Ethics at Georgetown University, Walters joined the Kennedy Institute in 1971 as its first faculty member appointed to a multi-year term by the new Director, Andre Hellegers, and has remained affiliated with the Institute ever since. His academic training at Messiah College, Associated Mennonite Seminaries, University of Heidelberg, Free University of Berlin, and Yale University focused on religious studies culminating in a Ph.D. on just war theory that provided the moral foundation for his ongoing work. Rising through the academic ranks until becoming the Joseph P. Kennedy, Sr., Professor of Christian Ethics in 1993, Walters was also Director of the Kennedy Institute for a three-year period. In addition to teaching and mentoring during his tenure at the Institute, he was also a bioethics “builder.” He envisioned and implemented Bioethicsline, one of the first online, annotated databases for bioethics research in the world. Linked to the National Library of Medicine, Bioethicsline served as a portal to what would become the National Reference Center for Bioethics Literature, the largest resource of its kind in the world. During his tenure, the Kennedy Institute began housing the collections of past [End Page xi] bioethics commissions and advisory bodies and an innovative DNA Patent Database, an unusual project for a bioethicist. Walters was a recently appointed Associate Professor when the editors and contributors to this special issue of KIEJ first encountered him as graduate students and colleagues in the early 1980s. Generations of students and colleagues have subsequently benefitted from his wisdom and gracious mentoring, but so too have countless federal agencies, departments, advisory committees, and working groups that he assisted as a consultant, member, or chair. Walters was involved in many of the most significant bioethics policy discussions occurring in the U.S. from the 1970s through the 2000s. He was a consultant to the National Institute of Child Health and Human Development, the DHEW Ethics Advisory Board, and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, for whom he prepared a key background paper on fetal research and participated in the development of its Belmont Report. He served for three terms on the NIH Recombinant DNA Advisory Committee, chairing the committee’s Working Group on Human Gene Therapy, which established review criteria for clinical gene transfer research and is still functioning four decades later. He chaired the NIH Human Fetal Tissue Transplantation Research Panel; sat on the Ethical, Legal and Social Implications Research Planning and Evaluation Group Program of the National Human Genome Research Institute; was a member of the Bioethics Committee of the National March of Dimes, the DHEW Secretary’s Task Force on Compensation of Injured Research Subjects, and as a committee member of Institute of Medicine studies on AIDS and vaccine development. He was an influential advisor and consultant to the Congressional Office of Technology Assessment, Office for Protection from Research Risks, and two presidential bioethics commissions. In addition to his policy influence, he is a prolific writer and aggregator of resources for use by others. Walters is responsible for creating and co-editing with Tamar Joy Kahn and Doris Mueller Goldstein thirty-five volumes of the Bibliography of Bioethics...

The RAC Retires after a Job Well Done

Genetic Engineering & Biotechnology NewsVol. 39, No. 1 OpinionThe RAC Retires after a Job Well DoneThe Recombinant DNA Advisory Committee is gracefully ceding oversight duties to IRBs and the FDAJames M. WilsonJames M. WilsonJames M. Wilson, MD, PhD, is the director of the Gene Therapy Program, the Rose H. Weiss Professor and Director of the Orphan Disease Center, and a professor of medicine and pediatrics at the Perelman School of Medicine, University of Pennsylvania. He is also the editor of Human Gene Therapy Clinical Development, published by Mary Ann Liebert, Inc.Search for more papers by this authorPublished Online:25 Jan 2019https://doi.org/10.1089/gen.39.01.05AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 39Issue 1Jan 2019 InformationCopyright © GEN PublishingTo cite this article:James M. Wilson.The RAC Retires after a Job Well Done.Genetic Engineering & Biotechnology News.Jan 2019.18-19.http://doi.org/10.1089/gen.39.01.05Published in Volume: 39 Issue 1: January 25, 2019PDF download

Is it ‘gene therapy’?

What, exactly, is therapy? Crystallizing a modern definition of has now become critically important on several fronts. Following the recent of passage the 21st Century Cures Act, FDA now relies on the term to give regulatory incentives to sponsors of certain ‘regenerative medicines’, including ‘gene therapies’. NIH Director Francis S. Collins and FDA Commissioner Scott Gottlieb recently announced that Recombinant DNA Advisory Committee (RAC) approval would no longer be required for because there is no longer sufficient evidence to claim that the risks of gene therapy are entirely unique and unpredictable. And in July 2018 FDA issued six draft guidance documents on but none with a substantially new definition. We review the contours ofthe term here, and propose that therapy— in the lay, scientific, and legal sense — should be defined as an intentional and expected permanent alteration of a specific DNA sequence of the cellular genome — that is, the sum of DNA that exists within a cell — for a clinical purpose. We also propose that gene therapy, as we define it, can be further categorized into at least three types: direct,compensatory, and augmenting. Defining gene therapy in this fashion would provide clarity to scientists and regulators alike.

Patients Suffer While the Science Establishment Resists Innovative Therapies

Human gene therapy has been up to now of a type that affects only the patient being treated; it has not modified sperm or eggs cells or embryos in a way that would constitute “germ line gene therapy” (GLGT) by creating a heritable change and affecting future generations. Preclinical research has progressed almost to the point where GLGT interventions will be possible with a reasonable likelihood of success, but such clinical trials are currently prohibited: NIH's Recombinant DNA Advisory Committee is not permitted even to consider such proposals, and the FDA cannot use appropriated funds to review such trials. Such absolute prohibitions are bad for patients and bad public policy.

"What's in a name?" CAR-T Gene Therapy.

With all due respect to Shakespeare, the impact of nomenclature should not be underestimated. Words are both effective and affective. They send a signal to the listener but may have an even more pronounced effect on the mind of the speaker. During a four-year stint I finished in 2010 on the National Institutes of Health Recombinant DNA Advisory Committee, the committee was repeatedly reminded that we should not speak of “gene therapy.” “Gene transfer research” (the preferred terminology) was resurgent in those years as the science made progress in safety and efficacy, and some time had passed since the tragic death of Jesse Gelsinger as a direct result of his participation in such a study. But by no means was the language of treatment considered appropriate—at least according to the powers that be at NIH. I suspect that investigators and patients who were considering enrollment on gene-transfer clinical trials might have had a different opinion. The former were attempting to develop treatments for a variety of diseases, and the latter wanted to benefit from the clinical science. Fast forward to August of 2017, when the Food and Drug Administration approved chimeric antigen receptor T cell (CAR-T) therapy for relapsed childhood acute lymphoblastic leukemia (ALL). This ex vivo genetic manipulation of a patient's own T-lymphocytes marks a major success in translational research, a landmark in cancer history, and a sign of good things to come in personalized medicine. Unfortunately, since CAR-T infusion is often associated with a life-threatening cytokine release syndrome, the approval was limited to a small number of centers with the expertise to manage this toxicity. Despite the risk, this is the most dazzling clinical science to come along in the nearly thirty years since I started my fellowship in pediatric oncology. And yes, with the imprimatur of the FDA, it is now acceptable in this case to use the term “gene therapy.” The question of what to name this activity reflects a longstanding debate in research ethics. Is it ever correct to talk about “therapeutic research?” What are the risks of promoting false hopes? During the era in which many aspire to build a learning health care system, perhaps one size does not fit all. High-risk, high-reward research like that which led to the development of CAR-T therapy seems to me to be categorically different from low-risk population-based research that leverages the electronic medical record and the power of big data. Thoughtful attention to such distinctions and to key transition points like FDA approval is the foundation for thinking about research, innovation, progress, and treatment in biomedicine. So, as long as there is a commitment to quality informed consent processes, count me in as comfortable talking about “therapeutic research.” The story of CAR-T doesn't end here, though. The cost is slated to be $475,000 per treatment course, with the expectation that one infusion will be sufficient. The chutzpah of charging a patient that much for getting an infusion of his or her own cells (albeit transformed) is considerable. Other recent breakthrough drugs for cystic fibrosis and hepatitis C have also been triggers for sticker shock. What are the justifications for such pricing, and how, if at all, might we think about limiting the cost? With a commitment to free-market approaches to drug development, we may be moving inexorably toward creating unobtainable cures. Progress against cancer happens in fits and starts. CAR-T represents a double-edged sword, a seemingly miraculous start coupled with a cautionary tale of clinical risk and cost. Having cared for many children who have died of ALL and having also seen how the late effects of our best treatments can impair quality of life, I pray that in the coming years we can maximize the benefits, minimize the cost and the harm, and help cancer patients survive and thrive. I would call that success.

What's the Use? Disparate Purposes of U.S. Federal Bioethics Commissions.

In the forty‐year history of U.S. bioethics commissions, these government‐sanctioned forums have often demonstrated their power to address pressing problems and to enable policy change. For example, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, established in 1974, left a legacy of reports that were translated into regulations and had an enormous practical impact. And the 1982 report Splicing Life, by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, became the basis for the National Institutes of Health's Recombinant DNA Advisory Committee as well as for the Food and Drug Administration's developing “Points to Consider” when contemplating the introduction of recombinant DNA into human beings. Some efforts of bioethics commissions, however, are not tightly connected to policy change or to outcomes directly linked to a specific report. While direct policy impact is indeed a useful metric for government bioethics commissions, it is not their only legitimate utility. For instance, bioethics commissions can also be incubators for deliberation on a hot topic, giving policy‐makers time to think through options while the political heat has some time to dissipate. Or a bioethics commission may stake out a position that enables a politician to take action while not necessarily following its recommendations.

U.S. Regulatory Challenges for Gene Editing

Researchers are now realizing the promise of molecular biology and genomic engineering. In the United States, President Obama has prioritized innovations in genomic research and therapies with funding infusions into national programs such as the Precision Medicine Initiative and the Cancer Moon Shot 2020. More than a decade after the completion of the Human Genome Project, our understanding of the human genome has now ushered us into the era of genetic modification capabilities known as genome editing, or gene editing. Building on the scientific foundation of recombinant DNA (rDNA) technology and human gene transfer research, gene editing enables the alteration of the genetic make-up in a manner that was previously only a theoretical possibility. Current gene editing technology improves on prior cellular-based therapies and gene therapies because it directly targets nucleotides in the defective gene. Following the discoveries of zinc finger nuclease (ZFN) and transcription activator-like effector nuclease (TALEN), a technique known as clustered regulatory-interspaced short palindromic repeat (CRISPR) is the most precise, efficient, and least expensive method of gene editing to date. First described in 2012, CRISPR-Cas9 uses the Cas9 enzyme and an RNA guide sequence to target a particular gene sequence, remove the faulty gene, and insert a new functioning gene and fuse the genetic strand back together. New variants of the CRISPR technology are currently being explored.CRISPR is garnering significant attention in the U.S. for both its relative simplicity over previous gene editing techniques and for its potential long-term commercial impacts. Shortly after the publication of the CRISPR discovery in Science, several leading gene editing scientists formed Editas Medicine in Cambridge, Massachusetts with a $43 million capital investment to design clinical trials based on the CRISPR and TALEN platforms. Reports indicate that Editas is projected to begin clinical trials by 2017 for a rare retinal disorder called Leber congenital amaurosis. But Editas is not the only player. Many of the early researchers involved in developing the CRISPR technology, including Jennifer Doudna (Caribou Biosciences) and Emmanuelle Charpentier (CRISPR Therapeutics) have also formed companies to develop applications using the CRISPR system. Recently on June 2016, the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC) approved a University of Pennsylvania protocol applying CRISPR) to genetically modify human T-cells in fifteen individuals suffering from multiple myeloma, melanoma, and sarcoma. Funded by the new Parker Institute for Cancer Immunotherapy, and led by Dr. Carl June, the clinical trial protocol has yet to be reviewed and approved by the appropriate institutional bodies and the U.S. Food and Drug Administration (FDA). Although in early stages of regulatory approval, the June 2016 decision of the RAC sheds new light on the ongoing debate regarding the ethical and legal implications of gene editing research. Concern about gene editing has inspired a broad global discussion in scientific and bioethics communities as to proper regulation and whether to halt future research on germline, or heritable, applications. This global discussion is nestled in the rich history of genetic research and the existing federal frameworks in place to oversee clinical trials, as well as the distinction between somatic and germline interventions. This article will examine the current regulatory landscape for gene editing research in the U.S. as positioned within the historical context and recent developments in this area.

Rethinking the Regulatory Infrastructure for Human Gene Transfer Clinical Trials.

The year 2015 marked the 40th anniversary of the Asilomar Conference leading to the first biosafety guidelines for research with recombinant DNA molecules,1 as well as the 25th anniversary of the first human gene transfer clinical trial approved by the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC).2 Since that time, the field has seen tremendous growth, with more than 1,500 human gene transfer (HGT) trials reviewed by the RAC to date. This has been accompanied by significant advances in the efficiency and efficacy of gene transfer tools, as well as our understanding of the biological risk profiles for these tools.

15. Development of Intrathecal scAAV9 Gene Therapy for Giant Axonal Neuropathy

Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disorder characterized by progressive sensory and motor neuropathy that presents as early as 3 years of age and with ultimate mortality during the second or third decade of life. GAN is caused by autosomal recessive loss-of-function mutations in the GAN gene that encodes the gigaxonin protein. Gigaxonin plays a role in the organization/degradation of intermediate filaments (IFs) and a pathological hallmark of GAN is large axonal swellings filled with disorganized aggregates of IFs. While GAN is primarily described as a peripheral neuropathy, diffuse pathology from disorganized IFs is found throughout the nervous system and other organ systems. An NIH-sponsored Phase I study is underway to test the safety of intrathecal (IT) administration of scAAV9/JeT-GAN to treat the mostsevere aspects of GAN, namely the motor and sensory neuropathy. Gigaxonin gene transfer is the first proposed therapy for GAN. Our group developed the vector to be used in the Phase I clinical trial, which is a self-complementary AAV serotype 9 vector carrying a codon-optimized human GAN transgene controlled by the minimal synthetic JeT promoter (scAAV9/JeT-GAN). Preclinical studies show that scAAV/JeT-GAN can restore the normal arrangement of IFs in patient fibroblasts within days in cell culture and by 3 weeks in GAN KO mice. The safety and biodistribution of scAAV9/JeT-GAN was investigated in mice and non-human primates that received a single IT overdose of scAAV9/JeT-GAN. No safety concerns were apparent from these animal studies, with the longest endpoint at 1 year post-injection. To further support the translation of this approach to human subjects, IT delivery of the scAAV9/JeT-GAN vector in GAN KO mice showed sustained levels of human gigaxonin expression in therapeutically-relevant areas for at least 48 weeks without evidence of toxicity. Furthermore, treated GAN KO mice have improved motor function and preservation of peripheral nerve ultrastructure. In all, the results of our preclinical studies attest to the safety of IT scAAV9/JeT-GAN delivery and the potential benefit to treated patients.During the review and public discussion of the clinical trial protocol, the NIH Recombinant DNA Advisory Committee (RAC) raised the concern of re-dosing patients with AAV vectors should the dose used prove to be safe but ineffective. Specifically, the RAC made the recommendation for researchers to evaluate the effect of re-administration in preclinical models in advance of this trial or preceding a subsequent trial. Pilot studies in wild-type mice show that repeat injection of scAAV9 vectors of the same dose and via the same IT route results in 70% less vector delivery of the second transgene to the brain, 70-95% less delivery to regions of the spinal cord and 55% less delivery to the sciatic nerve. This data suggests that alternative AAV capsids and/or routes of AAV delivery will need to be explored to enable effective re-dosing following an initial dose of scAAV9/JeT-GAN.

Genome Editing Technologies: Defining a Path to Clinic: Genomic Editing: Establishing Preclinical Toxicology Standards, Bethesda, Maryland 10 June 2014

Recently developed genomic editing technologies have the potential to be powerful tools for gene therapy because of their ability to inactivate genes, correct mutated sequences, or insert intact genes. While the genomic editing field is advancing at an exceptionally rapid pace, there remain key issues regarding development of appropriate preclinical assays to evaluate off-target effects and establish safety. In order to begin a dialogue on these issues, the National Institutes of Health (NIH) Office of Science Policy, in collaboration with several NIH-funded investigators and the NIH Recombinant DNA Advisory Committee, organized a workshop on 10 June 2014, in Bethesda, Maryland, to provide a forum to educate the scientific and oversight communities and the public on different genome editing technologies, clinical experiences to date, and the preclinical assays being developed to examine the precision of these tools and their suitability for clinical application.

The National Institutes of Health Oversight of Human Gene Transfer Research: Enhancing Science and Safety.

The National Institutes of Health (NIH) oversight of human gene transfer research, which is defined as the deliberate transfer of recombinant and/or synthetic nucleic acid molecules to humans, originates with the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). The NIH Guidelines, which were first published in the Federal Register almost 40 years ago, have been amended numerous times to remain responsive to scientific progress and to clearly define the responsibilities of NIH, the Recombinant DNA Advisory Committee (RAC), investigators, and institutions. Human gene transfer trials conducted at clinical sites in the United States (USA) are subject to the NIH Guidelines if they are conducted at, or sponsored by, an institution that receives any support for recombinant or synthetic nucleic acid research from the NIH. Human gene transfer trials conducted either in the USA or abroad are also subject to the NIH Guidelines if the investigational agent was developed with NIH funds and the institution that developed the investigational materials sponsors or participates in these projects. Trials are registered with the NIH Office Biotechnology Activities (OBA) and there are ongoing reporting requirements. Each new trial is reviewed by the RAC, and those that are novel or raise unique ethical or social issues are selected for review at quarterly public RAC meetings. The RAC also advises the NIH on policy and other matters relating to clinical gene transfer research and biosafety.

Cell-based interventions in utero: time to reconsider.

In 1999, the NIH Recombinant DNA Advisory Committee held a Gene Therapy Policy Conference on in utero gene transfer (NIH, 1999) and determined that it would be premature to undertake in utero gene transfer research in humans (RAC, 1999). Much has happened since then. Gene transfer research enrolling infants and very young children as patient-subjects has had results both beneficial and harmful in several conditions (Hacein-Bey-Abina et al., 2003; Aiuti et al., 2012; Corrigan-Curay et al., 2012). Some fetal surgical interventions have become accepted (Adzick et al., 2011). And much has been learned about the immune system and how pregnancy influences immune response. We now know a lot more about how much more there is to learn. Researchers in cell- and gene-based interventions are eager to move to human trials in order to continue the learning process. Yet funders and oversight bodies are reluctant to support cell-based intervention research in human fetuses. In this commentary we address probable reasons for this hesitancy, reasons to move forward with caution, and issues to address in planning first-in-human (FIH) trials of cell-based interventions in utero.

Future Oversight of Recombinant DNA Research

The National Institutes of Health (NIH) established the Recombinant DNA Advisory Committee (RAC) in 1974 in response to public concerns about the safety of manipulating genetic material through recombinant DNA (rDNA).1 Jesse Gelsinger’s death during a genetic therapy trial in 1999 further galvanized societal apprehensions.2 The RAC—a federal advisory committee to the NIH director—performs multiple functions: reviewing all gene transfer protocols, selecting specific protocols for public review, and acting as a national forum for rDNA research.3 Through its Gene Transfer Safety Assessment Board the RAC also surveils, aggregates, and analyzes adverse events across all human gene transfer trials.

Off the RAC

Off the RAC