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A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells

Nine hemophilia A dogs were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9%−11.3% of normal FVIII levels. In two of nine dogs, FVIII activi...

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Autores principales: Nguyen, Giang N., Everett, John K., Kafle, Samita, Roche, Aoife M., Raymond, Hayley E., Leiby, Jacob, Wood, Christian, Assenmacher, Charles-Antoine, Merricks, Elizabeth P., Long, C. Tyler, Kazazian, Haig H., Nichols, Timothy C., Bushman, Frederic D., Sabatino, Denise E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855056/
https://www.ncbi.nlm.nih.gov/pubmed/33199875
http://dx.doi.org/10.1038/s41587-020-0741-7
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author Nguyen, Giang N.
Everett, John K.
Kafle, Samita
Roche, Aoife M.
Raymond, Hayley E.
Leiby, Jacob
Wood, Christian
Assenmacher, Charles-Antoine
Merricks, Elizabeth P.
Long, C. Tyler
Kazazian, Haig H.
Nichols, Timothy C.
Bushman, Frederic D.
Sabatino, Denise E.
author_facet Nguyen, Giang N.
Everett, John K.
Kafle, Samita
Roche, Aoife M.
Raymond, Hayley E.
Leiby, Jacob
Wood, Christian
Assenmacher, Charles-Antoine
Merricks, Elizabeth P.
Long, C. Tyler
Kazazian, Haig H.
Nichols, Timothy C.
Bushman, Frederic D.
Sabatino, Denise E.
author_sort Nguyen, Giang N.
collection PubMed
description Nine hemophilia A dogs were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9%−11.3% of normal FVIII levels. In two of nine dogs, FVIII activity increased gradually starting about four years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of these integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A while emphasizing the importance of long-term monitoring for potential genotoxicity.
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spelling pubmed-78550562021-05-16 A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells Nguyen, Giang N. Everett, John K. Kafle, Samita Roche, Aoife M. Raymond, Hayley E. Leiby, Jacob Wood, Christian Assenmacher, Charles-Antoine Merricks, Elizabeth P. Long, C. Tyler Kazazian, Haig H. Nichols, Timothy C. Bushman, Frederic D. Sabatino, Denise E. Nat Biotechnol Article Nine hemophilia A dogs were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9%−11.3% of normal FVIII levels. In two of nine dogs, FVIII activity increased gradually starting about four years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of these integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A while emphasizing the importance of long-term monitoring for potential genotoxicity. 2020-11-16 2021-01 /pmc/articles/PMC7855056/ /pubmed/33199875 http://dx.doi.org/10.1038/s41587-020-0741-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Nguyen, Giang N.
Everett, John K.
Kafle, Samita
Roche, Aoife M.
Raymond, Hayley E.
Leiby, Jacob
Wood, Christian
Assenmacher, Charles-Antoine
Merricks, Elizabeth P.
Long, C. Tyler
Kazazian, Haig H.
Nichols, Timothy C.
Bushman, Frederic D.
Sabatino, Denise E.
A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells
title A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells
title_full A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells
title_fullStr A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells
title_full_unstemmed A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells
title_short A long-term study of AAV gene therapy in hemophilia A dogs identifies clonal expansions of transduced liver cells
title_sort long-term study of aav gene therapy in hemophilia a dogs identifies clonal expansions of transduced liver cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855056/
https://www.ncbi.nlm.nih.gov/pubmed/33199875
http://dx.doi.org/10.1038/s41587-020-0741-7
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