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AAV-S: A versatile capsid variant for transduction of mouse and primate inner ear.

ABSTRACT: Gene therapy strategies using adeno-associated virus (AAV) vectors to treat hereditary deafnesses have shown remarkable efficacy in some mouse models of hearing loss. Even so, there are few AAV capsids that transduce both inner and outer hair cells-the cells that express most deafness genes-and fewer still shown to transduce hair cells efficiently in primates. AAV capsids with robust transduction of inner and outer hair cells in primate cochlea will be needed for most clinical trials. Here, we test a capsid that we previously isolated from a random capsid library, AAV-S, for transduction in mouse and non-human primate inner ear. In both mice and cynomolgus macaques, AAV-S mediates highly efficient reporter gene expression in a variety of cochlear cells, including inner and outer hair cells, fibrocytes, and supporting cells. In a mouse model of Usher syndrome type 3A, AAV-S encoding CLRN1 robustly and durably rescues hearing. Overall, our data indicate that AAV-S is a promising candidate for therapeutic gene delivery to the human inner ear.

SUBMITTER: Ivanchenko MV

PROVIDER: S-EPMC8044388 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Adeno-associated viruses (AAVs) have recently emerged as the leading vector for retinal gene therapy. However, AAV vectors which are capable of achieving clinically relevant levels of transgene expression and widespread retinal transduction are still an unmet need. Using rationally designed AAV2-based capsid variants, we investigate the role of capsid hydrophilicity and hydrophobicity as it relates to retinal transduction. We show that hydrophilic, single amino acid (aa) mutations (V387R, W502H, E530K, L583R) in AAV2 negatively impact retinal transduction when heparan sulfate proteoglycan (HSPG) binding remains intact. Conversely, addition of hydrophobic point mutations to an HSPG binding deficient capsid (AAV2ΔHS) lead to increased retinal transduction in both mouse and macaque. Our top performing vector, AAV2(4pMut)ΔHS, achieved robust rod and cone photoreceptor (PR) transduction in macaque, especially in the fovea, and demonstrates the ability to spread laterally beyond the borders of the subretinal injection (SRI) bleb. This study both evaluates biophysical properties of AAV capsids that influence retinal transduction, and assesses the transduction and tropism of a novel capsid variant in a clinically relevant animal model.ImportanceRationally guided engineering of AAV capsids aims to create new generations of vectors with enhanced potential for human gene therapy. By applying rational design principles to AAV2-based capsids, we evaluated the influence of hydrophilic and hydrophobic amino acid (aa) mutations on retinal transduction as it relates to vector administration route. Through this approach we identified a largely deleterious relationship between hydrophilic aa mutations and canonical HSPG binding by AAV2-based capsids. Conversely, the inclusion of hydrophobic aa substitutions on a HSPG binding deficient capsid (AAV2ΔHS), generated a vector capable of robust rod and cone photoreceptor (PR) transduction. This vector AAV2(4pMut)ΔHS also demonstrates a remarkable ability to spread laterally beyond the initial subretinal injection (SRI) bleb, making it an ideal candidate for the treatment of retinal diseases which require a large area of transduction.

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AAV-S: A versatile capsid variant for transduction of mouse and primate inner ear.

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