American society of gene therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells

Long-Term Type VII Collagen Restoration to Human Epidermolysis Bullosa Skin Tissue

“…The board of directors of the American Society of Gene Therapy (ASGT) has provided a broad survey of the comprehensive data on preclinical and clinical studies using retroviral vectors and reported that insertional gene activation in mice was estimated as 1 in 4846. Furthermore, in large animal studies no animals exposed to helper-free vector preparations developed retrovirus-mediated insertional oncogenesis (Kohn et al, 2003). Likewise, we have never observed a spontaneous carcinoma in all our experience with regenerated human skin grafts prepared from retrovirally transduced human keratinocytes (Choate et al, 1996a,b;Deng et al, 1997Deng et al, , 1998Seitz et al, 1999;Robbins et al, 2001).…”

Successes and risks of gene therapy in primary immunodeficiencies

“…More than 40 human clinical trials have used retroviral vectors to transfer marker genes, anti-HIV genes, genes conferring resistance to cancer chemotherapy, and genes to correct inherited disorders. 78 No adverse effects from gene transfer have been observed outside of the French XSCID gene therapy trial, even with follow-up for more than 10 years in some cases. However, most of these studies achieved only very low levels of transduction that did not persist.…”

“…Except for one study describing myeloid leukemia in mice receiving mouse bone marrow transduced with a truncated nerve growth factor receptor gene, 78 animal studies in which HSCs have been transduced with replicationincompetent retroviral vectors have not shown deleterious effects attributable to the integration of the gene vector. More than 40 human clinical trials have used retroviral vectors to transfer marker genes, anti-HIV genes, genes conferring resistance to cancer chemotherapy, and genes to correct inherited disorders.…”

Recombinant AAV2 transduction of primitive human hematopoietic stem cells capable of serial engraftment in immune-deficient mice

“…The capacity of stem cells to both self-renew and give rise to differentiated progeny makes them excellent targets for the long-term correction of genetic diseases. However, safe and effective gene transfer into this rare population of cells has remained elusive, and studies to date have been beset with problems of low transduction frequencies and subtherapeutic efficacy (1,2). In particular, the unexpected leukemic transformation of transduced cells in three patients treated with oncoretrovirus vectors for X-linked severe combined immunodeficiency (SCID) (3,4) and the potential pathogenicity of other vector systems used underscore the need for continued exploration of alternate strategies for stem cell gene transfer.…”