The invention relates to synthetic adeno-associated virus capsids targeted to the liver and vims vectors comprising the same. The invention further relates to methods of using the vectors to target the liver and provide liver-specific expression, as well as transduce human primary hepatocytes and cell lines.

Provided herein are improved rAAV (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of ocular disorders or CNS disorders wherein the rAAV comprise one or more substitutions of amino acids that interact with heparan sulfate proteoglycan. The invention provides methods for improved transduction of retinal cells and methods for treating ocular diseases with improved compositions of rAAV particles. Further provided herein are improved recombinant adeno-associated virus (rAAV) (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of disorders of the CNS. The invention provides methods for delivering the rAAV to the CNS, methods for treating disorders of the CNS with improved compositions of rAAV particles, and kits for delivering the rAAV to the CNS and/or treating a CNS disorder.

Provided herein are improved rAAV (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of ocular disorders or CNS disorders wherein the rAAV comprise one or more substitutions of amino acids that interact with heparan sulfate proteoglycan. The invention provides methods for improved transduction of retinal cells and methods for treating ocular diseases with improved compositions of rAAV particles. Further provided herein are improved recombinant adeno-associated virus (rAAV) (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of disorders of the CNS. The invention provides methods for delivering the rAAV to the CNS, methods for treating disorders of the CNS with improved compositions of rAAV particles, and kits for delivering the rAAV to the CNS and/or treating a CNS disorder.

Disclosed herein include methods, compositions, and kits comprising variant AAV capsids. Variant capsid proteins, including guided variant capsid proteins, tandem multimers, and/or HI loop variant capsid proteins, are provided in some embodiments. The variant capsid proteins disclosed herein are capable of assembling into a variant AAV capsid with an expanded size (e.g., diameter) and/or genetic cargo capacity. Methods generating recombinant AAV (rAAV) with expanded capsids are provided. Methods of treating diseases and disorders using said rAAV are also disclosed.

Disclosed herein include methods, compositions, and kits comprising variant AAV capsids. Variant capsid proteins, including guided variant capsid proteins, tandem multimers, and/or HI loop variant capsid proteins, are provided in some embodiments. The variant capsid proteins disclosed herein are capable of assembling into a variant AAV capsid with an expanded size (e.g., diameter) and/or genetic cargo capacity. Methods generating recombinant AAV (rAAV) with expanded capsids are provided. Methods of treating diseases and disorders using said rAAV are also disclosed.

Methods and compositions are provided for intravitreally delivering a polynucleotide to cone photoreceptors. Aspects of the methods include injecting a recombinant adeno-associated virus comprising a polynucleotide of interest into the vitreous of the eye. These methods and compositions find particular use in treating ocular disorders associated with cone dysfunction and/or death.

Provided herein are improved rAAV (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of ocular disorders or CNS disorders wherein the rAAV comprise one or more substitutions of amino acids that interact with heparan sulfate proteoglycan. The invention provides methods for improved transduction of retinal cells and methods for treating ocular diseases with improved compositions of rAAV particles. Further provided herein are improved recombinant adeno-associated virus (rAAV) (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of disorders of the CNS. The invention provides methods for delivering the rAAV to the CNS, methods for treating disorders of the CNS with improved compositions of rAAV particles, and kits for delivering the rAAV to the CNS and/or treating a CNS disorder.

Provided herein are improved rAAV (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of ocular disorders or CNS disorders wherein the rAAV comprise one or more substitutions of amino acids that interact with heparan sulfate proteoglycan. The invention provides methods for improved transduction of retinal cells and methods for treating ocular diseases with improved compositions of rAAV particles. Further provided herein are improved recombinant adeno-associated virus (rAAV) (e.g., rAAV2, rAAVrh8R, etc.) for enhanced gene therapy of disorders of the CNS. The invention provides methods for delivering the rAAV to the CNS, methods for treating disorders of the CNS with improved compositions of rAAV particles, and kits for delivering the rAAV to the CNS and/or treating a CNS disorder.

Provided herein are methods for enhancing gene therapy in an individual by administering an IRAK degrader with the gene therapy to suppress innate immunity to the gene therapy. In some embodiments, the gene therapy uses an adeno-associated virus (AAV) vector, an adenovirus vector, a lentivirus vector, a Herpes simplex virus (HSV) vector or a lipid nanoparticle. Also provided herein are methods for selecting an individual for treatment with an IRAK degrader in combination with a gene therapy agent.

A method of preparing a chimeric virus comprising bocavirus capsid protein (VP) and a recombinant adeno-associated (AAV) viral genome, and isolated mutant bocavirus genomes, are provided.