title: Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis.
abstract: Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease with early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects are characterized at the most severe end of the LCA spectrum. The rapid photoreceptor degeneration and vision loss observed in the LCA patient population are mimicked in a mouse model lacking AIPL1. Using this model, we evaluated if gene replacement therapy using recent advancements in adeno-associated viral vectors (AAV) provides advantages in preventing rapid retinal degeneration. Specifically, we demonstrated that the novel self-complementary Y733F capsid mutant AAV2/8 (sc-Y733F-AAV) provided greater preservation of photoreceptors and functional vision in Aipl1 null mice compared with single-stranded AAV2/8. The benefits of sc-Y733F-AAV were evident following viral administration during the active phase of retinal degeneration, where only sc-Y733F-AAV treatment achieved functional vision rescue. This result was likely due to higher and earlier onset of Aipl1 expression. Based on our studies, we conclude that the sc-Y733F-AAV2/8 viral vector, to date, achieves the best rescue for rapid retinal degeneration in Aipl1 null mice. Our results provide important considerations for viral vectors to be used in future gene therapy clinical trials targeting a wider severity spectrum of inherited retinal dystrophies.
authors: Center for Neuroscience, West Virginia University, Morgantown, WV 26505, USA.
authors: Cristy A
authors: CA
authors: Ku
authors: Vince A
authors: VA
authors: Chiodo
authors: Sanford L
authors: SL
authors: Boye
authors: Andrew F X
authors: AF
authors: Goldberg
authors: Tiansen
authors: T
authors: Li
authors: William W
authors: WW
authors: Hauswirth
authors: Visvanathan
authors: V
authors: Ramamurthy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002213:Capsid / Q000378:metabolism*; D036022:Capsid Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000627:therapeutic use; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics* / Q000528:radiation effects; D005136:Eye Proteins / Q000235:genetics / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000150:complications / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D008027:Light; D051379:Mice; D009154:Mutation / Q000235:genetics*; D012160:Retina / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D012162:Retinal Degeneration / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014785:Vision, Ocular / Q000502:physiology* / Q000528:radiation effects
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C498604:Aipl1 protein, mouse; D036022:Capsid Proteins; D002352:Carrier Proteins; D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6