Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species.

Autor:	Tabebordbar M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: tabebord@fas.harvard.edu., Lagerborg KA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA., Stanton A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Program in Virology, Harvard Medical School, Boston, MA 02115, USA., King EM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Ye S; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Tellez L; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Krunnfusz A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Tavakoli S; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA., Widrick JJ; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Messemer KA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA., Troiano EC; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Moghadaszadeh B; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Peacker BL; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA., Leacock KA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA., Horwitz N; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA., Beggs AH; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Wagers AJ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA. Electronic address: amy_wagers@harvard.edu., Sabeti PC; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Organismic and Evolutionary Biology, FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: pardis@broadinstitute.org.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Sep 16; Vol. 184 (19), pp. 4919-4938.e22. Date of Electronic Publication: 2021 Sep 09.
DOI:	10.1016/j.cell.2021.08.028
Abstrakt:	Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers. Competing Interests: Declaration of interests P.C.S. is a co-founder of, shareholder in, and advisor to Sherlock Biosciences, Inc, as well as a board member of and shareholder in Danaher Corporation. M.T. and P.C.S. are recipients of a sponsored research award from Sarepta Therapeutics. M.T. is a co-founder of, shareholder in, and advisor to Kate Therapeutics. A.H.B. has received sponsored research support from NIH, MDA (USA), AFM Telethon, Alexion Pharmaceuticals Inc., Audentes Therapeutics Inc., Dynacure SAS, and Pfizer Inc. He has consulted and received compensation or honoraria from Asklepios BioPharmaceutical Inc, Audentes Therapeutics, Biogen, F. Hoffman-La Roche AG, Kate Therapeutics, GLG Inc, and Guidepoint Global and holds equity in Ballard Biologics and Kate Therapeutics. A.J.W. is a consultant to Frequency Therapeutics, a recipient of a sponsored research award from Sarepta Therapeutics, and a co-founder of Elevian, a company that aims to develop medicines to restore regenerative capacity, and advises, receives sponsored research support, and holds private equity in the company. M.T., S.Y., and P.C.S. are inventors on patent applications filed by the Broad Institute related to this work. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu