Future Directions and Resource Needs for NHLBI Gene Therapy Research

March 15 - 16 , 2022


The National Heart, Lung, and Blood Institute (NHLBI) convened a two-day virtual workshop entitled, “Future Directions and Resource Needs for NHLBI Gene Therapy Research” on March 15 and 16, 2022.

The purpose of this workshop was to bring together experts in the basic science, preclinical, translational, and clinical aspects of gene therapy to evaluate the current, near, and future directions of the field of gene therapy, including the evolving role of gene editing. The panel was asked to address the hurdles faced in advancing research on emerging gene therapies for heart, lung, blood, and sleep disorders and to identify the resources, training, and other opportunities to advance the field.


Over the past 30 years, NHLBI has been a leader in gene therapy research and has proactively provided investigators with research resources through various programs. One such program, the NHLBI Gene Therapy Resource Program (GTRP), was first launched in June 2007 and is now in its third iteration, which runs through December 2023. In order to develop the next generation gene therapy resource and support program, NHLBI sought input from the research community.


The meeting opened with presentations on the history of the GTRP and the evolution of the field of gene therapy, followed by discussions in four main thematic areas. Synopses of these discussions are presented below.

The State of the Science

Autologous hematopoietic stem cell (HSC) gene therapy is a well-established paradigm and researchers have conducted 15 trials with lentivirus/HSC agents for various disorders with positive results, though some adverse events have also occurred. Therefore, constant vigilance, transparency and collaboration for risk mitigation to maximize patient safety remains the highest priority in gene therapy research.

The field now has a line of sight for gene therapy treatments, but rare disease programs have been deprioritized in industry, and the time and costs related to the development of gene therapies for ultra-rare diseases are even more challenging. Therefore, because industry funding is not steady, other sources of support for gene therapy research and development remain critical.

The gene therapy field is now in the age of editing genes, which will transform medicine. Gene editing has a robust technical base with expanding clinical use and solid delivery innovation. In vivo gene editing is being used in clinical-stage applications for various inherited diseases, but researchers continue to define its associated immune responses. In the area of ex vivo gene editing, some experimental agents show clinical efficacy, and researchers are studying precision editing and next-generation CRISPR (clustered regularly interspaced short palindromic repeats) tool. However, many good preclinical findings are not moving to the translational/clinical phase due to challenges navigating the somewhat siloed preclinical and regulatory landscape, as well as due to bottlenecks in the Chemistry, Manufacturing, and Control (CMC) space and supply chain issues. Additionally, in order to realize the promise of CRISPR and other gene editing technologies as future therapies, the regulatory framework will need to be updated. There is a unique role for federal and state governments in supporting and enabling clinical development in the academic/nonprofit sector.

Emerging Technologies and Future Directions

Scientists have made remarkable progress across various classes of genome editors-nucleases, base editors, transposases/recombinases, and prime editors. This has led to an explosion of future therapeutic possibilities. These are being studied in animal models, with ongoing improvements in the underlying technologies. CRISPR-free base editors enable the first precision editing of mitochondrial DNA. A major technical advance has been efficient gene modification by homology-directed repair in primary hematopoietic cells. Engineered plasma cells could serve as a therapeutic delivery platform for many different conditions, and it may be possible to engineer thymic regulatory T cells or B cells.

In order to realize the possibilities of gene and cell therapies, there should be an intersection of the following three areas: control of DNA repair outcomes; delivery to the required cells and tissues; and specificity for the DNA target. Engineered lipid nanoparticles as a gene therapy delivery technology (e.g., for nucleic acids and mRNA) have the potential to target a wide variety of cells and tissues. Intracellular delivery of nucleic acids (e.g., siRNA) will revolutionize medicine, and research on how they can be delivered inside of cells in vivo is ongoing. Polymer nanoparticles are an exciting technology because they can silence multiple genes simultaneously. Genetic diversification and selection can be harnessed to solve complex problems with gene delivery systems. Researchers have used this approach to engineer adeno-associated viral vectors with enhanced efficiency, targeted delivery, and immune evasion.

Challenges in Clinical Translation and Implementation

Adaptive immunity can be a barrier to effective gene therapy, preventing the use of gene therapy more than once in some cases. Therefore, researchers need to understand how pre-existing immunity affects the response to gene therapy. Patients may also show classical complement pathway activation that could complicate the situation. Researchers can perform immune profiling with commercially available products and try to manage the immune response of patients. Immune modulation with agents such as rituximab and sirolimus, and antibody blockade if needed, may allow for repeat dosing and mitigate the immune responses to the transgene in null mutations.

Although academic researchers can obtain funding for basic science and proof-of-concept studies in gene therapy, further studies to support IND applications are difficult to fund through traditional federal grant funding mechanisms. Significant other hurdles include: regulatory affairs assistance is needed by many academic investigators; large amounts of clinical-grade vector and gene editing agents are needed for clinical research and these are expensive; and it is difficult to secure funding for grant funding for GLP animal studies examining dose response, toxicity, and biodistribution. Panelists also noted that securing funding for the required 15-year follow-up of participants in some gene therapy trials is also quite challenging for academic physicians.

For gene therapy clinical trials, it is essential to have good natural history data as a comparator for the disease under study as it is difficult to include a placebo arm. To evaluate gene therapy platforms, the field needs studies that show improvement of functioning (e.g., in neurodevelopmental or neurodegenerative diseases) rather than stabilization. The analytical characterization of gene therapy products, which the FDA expects, is in the very early stages and needs to be more robust and precise. Organized leadership of this effort would benefit the entire gene therapy community.

To advance gene therapy, the field must share safety data. Some researchers have suggested that safety may be improved by understanding the effects of preexisting clonal hematopoiesis of indeterminate potential (CHIP) or unintended off-target mutations on cancer risk. Participants were mindful about CHIP and related ongoing research, but they did not reach agreement on whether it should be an exclusion criterion for all trials.

From There to Here, and Where the Field is Going: Identifying Research Gaps and Opportunities

Adeno-associated virus (AAV) vectors are a very good delivery method for gene therapy as they are safe, somewhat efficient, have stable expression, are manufacturable, and have shown efficacy in multiple clinical trials. However, optimization of these vectors is needed in several areas, including: delivery efficiency, manufacturing capacity, and better gene regulation.

Intracellular delivery of nucleic acids will revolutionize medicine, but a crucial challenge is determining the best delivery method to the inside of cells in vivo. It will be important to determine the organs most amendable to targeting. Scientists have achieved dramatic improvements in delivery potency over time through iterative ionizable lipid engineering, and now the field has formulations that are very low dose yet sufficiently potent to knock down a gene in the liver. Additionally, polymer nanoparticles have great potential and have been shown in animal studies to silence multiple genes. Also, there is a promising pipeline of new reagents moving forward for regulatory approval, especially new bone marrow conditioning regimens for immunocompromised patients.

Regarding in vivo gene therapy and gene editing, the field is making strides with great findings to come. Clinical concerns are generally from gene therapy legacy programs since gene therapy technology has improved and scientists now have a better understanding of human biology. It will be important to focus on programs that have a high chance of succeeding as technologies emerge and progress. Also, there should be a focus on diseases with unmet treatment need. Biomarkers will be critical and provide some indication whether gene editing is affecting a biological pathway in a clinical trial. Workshop participants noted that experimental medicine could generate a great deal of knowledge from data on humans. They noted that the California Institute of Regenerative Medicine (CIRM) and the NIH Common Fund Somatic Cell Genome Editing program might offer opportunities or models for partnerships.

Summary of Research Opportunities

The workshop participants identified the following areas of opportunity in the gene therapy field:

  • Advances in the production of GMP-grade vectors, nanoparticles, proteins, and mRNA, with flexibility to include emerging technologies and assistance with meeting CMC challenges could allow investigators to advance from innovation to the clinic faster, as well as facilitate better outcomes of the gene transductions with lower viral loads.
  • A centralized biobank/repository for gene therapy with standardized procedures for banking and withdrawal for analysis of specimens from humans who received gene therapy agents could facilitate investigators’ understanding of the natural history of conditions and responses to investigational agents.
  • A mechanism to provide and share centrally-sourced critical reagents could allow more cost-effective investigations among many different researchers and could be particularly important when samples need to be analyzed such as when adverse events occur.
  • A facility for large animal studies, particularly those that will benefit the field broadly such as sophisticated monitoring of immune responses, and continued efforts to improve the supply of non-human primates for research, could help provide better predictions of the effects of the investigational gene therapy agents given greater genome homology with human than small animal models afford. This will also help FDA to better interpret/evaluate the outcomes of the animal tests when providing regulatory guidance.
  • Expert assistance with safety analyses and a mechanism to share clinical safety data, regulatory affairs assistance and guidance specific to each stage of translational advancement, and assistance with intellectual property and commercialization issues could allow investigators to more rapidly advance their products along the translational pathway.
  • Coordinated long-term follow-up of individuals who received gene therapy agents could alleviate duplicative efforts and siloed information, leading to improved understanding of the long-term safety data from gene therapy clinical trials.
  • Expanded participation across the various NIH Institutes and Centers and a resource, perhaps through the NIH Rare Diseases Clinical Research Network (RDCRN), to capture and collate natural history data on orphan/rare diseases could result in an expansion of the diseases studied and a better understanding of the manifestations of disease. This could lead to better clinical trial readiness, biomarker identification, and determination of outcome measures that enhance our understanding of the efficacy of the gene therapy.
  • A readily accessible matchmaking portal that provides transparent and accurate information to the rare disease community could more readily connect parents/patients, clinicians, and researchers thereby facilitating the development of, and enrollment into, clinical trials for rare/neglected diseases.

Publication Plans

The workshop participants plan to prepare a manuscript that highlights the research gaps, opportunities, and resource needs for publication in a peer-reviewed journal.

Workshop Chair

Terence R. Flotte, M.D., University of Massachusetts

NHLBI Workshop Planning Group

Cheryl L. McDonald, M.D.
Pankaj Qasba, Ph.D.
Rahul G. Thakar, Ph.D.

Workshop Speakers/Moderators in Order Listed in Workshop Agenda

Donald B. Kohn, M.D., University of California, Los Angeles
James M. Wilson, M.D., Ph.D., University of Pennsylvania
Fyodor Urnov, Ph.D., University of California, Berkeley
Matthew Porteus, M.D., Ph.D., Stanford Medicine
David R. Liu, Ph.D., Harvard University
David Rawlings, M.D., Seattle Children’s Hospital and University of Washington
Shengdar Q. Tsai, Ph.D., St. Jude Children’s Research Hospital
Michael J. Mitchell, Ph.D., University of Pennsylvania
Gang Bao, Ph.D., Rice University
Barry J. Byrne, M.D., Ph.D., University of Florida
William Pu, M.D., Boston Children’s Hospital
Punam Malik, M.D., University of Cincinnati College of Medicine and Cincinnati Children’s Hospital
Hans-Peter Kiem, M.D., Ph.D., Fred Hutchinson Cancer Research Center and the University of Washington
David A. Williams, M.D., Dana Farber Cancer Institute and Boston Children’s Hospital
Richard Colvin, M.D., Ph.D., bluebird bio
David Schaffer, Ph.D., University of California, Berkeley
Daniel G. Anderson, Ph.D., Massachusetts Institute of Technology