A Changing World in Gene Therapy Research: Exciting Opportunities for Medical Advancement and Biosafety Challenges

Abstract

Introduction: We previously reported on the United States' regulatory environment evolving to accommodate an emerging boom in gene therapy research. Several important developments have transpired in the 2 years since that article was published, including the coronavirus disease 2019 (COVID-19) pandemic and the drive for large-scale testing of vaccines containing recombinant or synthetic nucleic acid molecules. This report highlights key developments in the field with a focus on biosafety and issues of note to biosafety professionals with responsibilities over clinical research. Discussion: We provide guidance for performing risk assessments on the currently approved gene therapy products as well as the most utilized types of investigational products in clinical trials. Areas of focus include the prominent approaches utilized in the three major areas of research: oncology, infectious diseases, and rare diseases. Conclusion: The COVID-19 pandemic has created several opportunities for continued growth in gene therapy. National vaccination campaigns will result in greater public acceptance of gene therapy research. Technological advancements that made the vaccine race possible will spur the next generation of research. Advancements born in the developed world set the stage for the creation of therapeutics to treat greater numbers in the developing world and have the potential for massive benefits to global public health. Biosafety professionals and Institutional Biosafety Committees play key roles in contributing to the safe evidence-based advancement of gene therapy research. Biosafety professionals responsible for clinical research oversight must be aware of emerging technologies and their associated risks to support the safe and ethical conduct of research.

Keywords: Food and Drug Administration (FDA); Institutional Biosafety Committee (IBC); NIH guidelines; gene therapy; investigational new drug (IND).

Figure 1.

Gene therapy research caused a growth in IBCs registered with the NIH. (A) Gene therapy IND applications submitted per year to the FDA. Data adapted with permission from Peter Marks, Director, FDA CBER. (B) IBC registrations approved by the NIH OSP per year. Data adapted with permission from Kathryn Harris, NIH OSP. (C) Change in local versus externally administered IBCs registered with NIH OSP. CBER, Center for Biologics Evaluation and Research; FDA, Food and Drug Administration; IBCs, Institutional Biosafety Committees; IND, investigational new drug; NIH, National Institutes of Health; OSP, Office of Science Policy.

Figure 2.

CAR T cells: (A) Common structure of a CAR. (B) Autologous CAR T cells express endogenous TCR and HLA/MHC. (C) “Off-the-shelf”/universal CAR T cells are modified to prevent surface expression of the endogenous TCR and HLA/MHC to avoid graft versus host disease and rejection of the CAR T cells, respectively. CAR, chimeric antigen receptor; HLA, human leukocyte antigen; MHC, major histo-compatibility complex; TCR, T cell receptor.