Compositions and methods are provided for treating Leber congenital amaurosis (LCA) in a subject. In one aspect, a recombinant adeno-associated viral vector is provided which includes a nucleic acid molecule comprising a sequence encoding Lebercilin. In another aspect, Lebercilin has an amino acid sequence of SEQ ID NO: 1. In yet another aspect, the nucleic acid molecule has a sequence of SEQ ID NO: 3 or a variant thereof. In desired embodiments, the subject is human, cat, dog, sheep, or non-human primate.

This disclosure provides compositions and methods for delivering a viral composition to cells, e.g., for cell surface receptor-mediated uptake, and enhanced viral transduction. Viral transduction can be achieved via a bifunctional bridging composition that includes a moiety that binds to a cell surface receptor ligand and a linked bridging moiety that binds to a viral composition. Also provided are modified viral compositions comprising a bridging composition specifically bound via its bridging moiety to the viral composition. Modified viral compositions and methods for reducing levels or titers of neutralizing antibodies in a subject in need of viral therapy, e.g., gene therapy, are provided. In some embodiments, the modified viral composition includes empty viral particles that bind and internalize neutralizing autoantibodies. Modified viral compositions including empty viral particles can be administered prior to viral therapy. Also provided are pharmaceutical compositions and kits including a bifunctional bridging composition and/or modified viral compositions.

The present invention provides a polyploid adeno-associated virus (AAV) capsid, wherein the capsid comprises capsid protein VP1, wherein said capsid protein VP1 is from one or more than one first AAV serotype, wherein said capsid protein VP2 is from one or more than one first AAV serotype and capsid protein VP3, wherein said capsid protein VP3 is from one or more than one second AAV serotype and wherein at least one of said first AAV serotype is different from at least one of said second AAV serotype and is different from at least one of said third AAV serotype, in any combination.

Genetically modified compositions, such as adeno-associated viral vectors and primary cells, for treating various conditions and diseases. Disclosed are also modified adeno-associated viruses for the treatment of cancer. Also disclosed are the methods of making and using the genetically modified compositions in treating various diseases, conditions, and cancer.

Disclosed herein are methods and compositions for gene therapy, in particular, methods and compositions related to alterations in a capsid protein sequence for altering permissiveness of a promoter within a cell when the promoter and the capsid protein are present within the cell and the capsid protein and the promoter are in the context of a recombinant adeno-associated virus (AAV) particle.

The present disclosure provides recombinant adeno-associated virus (rAAV) virions with an engineered capsid protein. In particular, the disclosure provides AAV9 virions with engineered AAV9 capsid, AAV5/9 chimeric capsid or combinatory capsid that achieves increased transduction efficiency in cardiac cells, increased cell-type selectivity, and/or other desirable properties.

The present invention is directed to viral vectors and methods of their production and use.

Provided herein are methods for determining the serotype of a virus particle and/or or determining the heterogeneity of a virus particle (e.g., an AAV particle). In other embodiments, the invention provides methods to determine the heterogeneity of AAV particles. In some aspects, the invention provides viral particles (e.g., rAAV particles) with improved stability and/or improved transduction efficiency by increasing the acetylation and/or deamidation of capsid proteins.

Non-human animal cells and non-human animals comprising a humanized Asgr1 locus and methods of using such non-human animal cells and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized Asgr1 locus express a human ASGR1 protein or an Asgr1 protein, fragments of which are from human ASGR1. Methods are provided for using such non-human animals comprising a humanized Asgr1 locus to assess in vivo efficacy of human-ASGR1-mediated delivery of therapeutic molecules or therapeutic complexes to the liver and to assess the efficacy of therapeutic molecules or therapeutic complexes acting via human-ASGR1-mediated mechanisms.

Provided herein are variant adeno-associated virus (AAV) capsid proteins having one or more modifications in amino acid sequence relative to a parental AAV capsid protein, which, when present in an AAV virion, confer increased infectivity of one or more types of retinal cells as compared to the infectivity of the retinal cells by an AAV virion comprising the unmodified parental AAV capsid protein. Also provided are recombinant AAV virions and pharmaceutical compositions thereof comprising a variant AAV capsid protein as described herein, methods of making these rAAV capsid proteins and virions, and methods for using these rAAV capsid proteins and virions in research and clinical practice, for example in, e.g., the delivery of nucleic acid sequences to one or more cells of the retina for the treatment of retinal disorders and diseases.