Remodeling the NGVL Program to Meet Contemporary Needs
Authors: Anthony R Hayward
Journal: Molecular Therapy (2007)

National Institutes of Health (NIH) initiatives to support studies of gene therapy peaked in the 1990s as attempts were made to build on experience gained with adenosine deaminase deficiency. The National Center for Research Resources' (NCRR) National Gene Vector Laboratory (NGVL) program was started in 1995 to encourage the production of clinical-grade vectors under Good Manufacturing Practice conditions and to create a forum for the exchange of ideas, experiences, and data among experts in the field. The setbacks in the treatment of ornithine transcarbamylase deficiency and X-linked severe combined immunodeficiency temporarily slowed advances, but new highly targeted initiatives were published by categorical NIH institutes in 2006. These included the National Heart, Lung, and Blood Institute's “New Approaches to Non-Viral Systems for Gene Transfer Applications for Heart, Lung, and Blood Diseases” (http://grants.nih.gov/grants/guide/pa-files/PA-06-243.html) and the development of primate models, such as “RNAi and Therapeutic Targeting to Model Gene Therapy in Monkeys: The 6th Annual Gene Therapy Symposium for Heart, Lung, and Blood Diseases Focus Topic” (http://www.gts.ucdavis.edu/2007.htm). The National Cancer Institute has also reported successes, as in a 2006 article in Science, “Cancer Regression in Patients after Transfer of Genetically Engineered Lymphocytes.” Advances in these defined areas have been accompanied by a reduction in the overall number of NIH institutes supporting gene therapy research, and this change in balance required that NCRR re-evaluate the role of the NGVL. It soon became clear that the number of NIH Institutes and Centers availing themselves of NGVL resources had fallen below a level at which NCRR could reasonably be said to be meeting its mission to “accelerate and enhance research along the entire continuum of biomedical science, to stimulate basic research to develop versatile new technologies and methods that help researchers to study virtually every human disease.”New vector-production resources have been brought on line since 1995, and patient safety, including the potential for delayed adverse events, still has the highest priority. The U.S. Food and Drug Administration (FDA) recommends that human subjects exposed to the risk of delayed toxic effects be observed for as long as 15 years (for U.S. FDA guidance, see “Gene Therapy Clinical Trials—Observing Subjects for Delayed Adverse Events,” http://www.fda.gov/cber/gdlns/gtclin.htm), so resources to archive biologic material are essential in the investigation of delayed toxic effects related to exposure to a gene therapy product. Furthermore, acute toxicity associated with gene therapy may stem from the vector, and gene therapy products often use vectors that are the same as or similar to vectors for which the NGVL currently has data from toxicology and biodistribution studies. Making the data from these and other studies available in a searchable toxicology and biodistribution database (as is proposed for the National Gene Vector Biorepository and Coordinating Center (P40), RFA-RR-07-002; see http://www.ncrr.nih.gov/ncrrprog/clindir/NGVL.asp) should save researchers both time and resources. If this new NCRR initiative can complement the new opportunities for gene therapy being offered through the categorical institutes, then it will go some way toward addressing the investigators' needs. National Institutes of Health (NIH) initiatives to support studies of gene therapy peaked in the 1990s as attempts were made to build on experience gained with adenosine deaminase deficiency. The National Center for Research Resources' (NCRR) National Gene Vector Laboratory (NGVL) program was started in 1995 to encourage the production of clinical-grade vectors under Good Manufacturing Practice conditions and to create a forum for the exchange of ideas, experiences, and data among experts in the field. The setbacks in the treatment of ornithine transcarbamylase deficiency and X-linked severe combined immunodeficiency temporarily slowed advances, but new highly targeted initiatives were published by categorical NIH institutes in 2006. These included the National Heart, Lung, and Blood Institute's “New Approaches to Non-Viral Systems for Gene Transfer Applications for Heart, Lung, and Blood Diseases” (http://grants.nih.gov/grants/guide/pa-files/PA-06-243.html) and the development of primate models, such as “RNAi and Therapeutic Targeting to Model Gene Therapy in Monkeys: The 6th Annual Gene Therapy Symposium for Heart, Lung, and Blood Diseases Focus Topic” (http://www.gts.ucdavis.edu/2007.htm). The National Cancer Institute has also reported successes, as in a 2006 article in Science, “Cancer Regression in Patients after Transfer of Genetically Engineered Lymphocytes.” Advances in these defined areas have been accompanied by a reduction in the overall number of NIH institutes supporting gene therapy research, and this change in balance required that NCRR re-evaluate the role of the NGVL. It soon became clear that the number of NIH Institutes and Centers availing themselves of NGVL resources had fallen below a level at which NCRR could reasonably be said to be meeting its mission to “accelerate and enhance research along the entire continuum of biomedical science, to stimulate basic research to develop versatile new technologies and methods that help researchers to study virtually every human disease.” New vector-production resources have been brought on line since 1995, and patient safety, including the potential for delayed adverse events, still has the highest priority. The U.S. Food and Drug Administration (FDA) recommends that human subjects exposed to the risk of delayed toxic effects be observed for as long as 15 years (for U.S. FDA guidance, see “Gene Therapy Clinical Trials—Observing Subjects for Delayed Adverse Events,” http://www.fda.gov/cber/gdlns/gtclin.htm), so resources to archive biologic material are essential in the investigation of delayed toxic effects related to exposure to a gene therapy product. Furthermore, acute toxicity associated with gene therapy may stem from the vector, and gene therapy products often use vectors that are the same as or similar to vectors for which the NGVL currently has data from toxicology and biodistribution studies. Making the data from these and other studies available in a searchable toxicology and biodistribution database (as is proposed for the National Gene Vector Biorepository and Coordinating Center (P40), RFA-RR-07-002; see http://www.ncrr.nih.gov/ncrrprog/clindir/NGVL.asp) should save researchers both time and resources. If this new NCRR initiative can complement the new opportunities for gene therapy being offered through the categorical institutes, then it will go some way toward addressing the investigators' needs.