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 ceils of the retina for the treatment of retinal disorders and diseases.

Disclosed herein are novel methods for administration of rAAV particles having enhanced transduction properties, comprising the pre-incubation and co-administration of AAV capsids and polyvinyl alcohol (PVA). The disclosed methods of rAAV particle administration have improved efficiency in transducing mammalian liver and hematopoetic cells in vivo. The disclosed methods are suitable for use with a variety of AAV capsid serotypes and presudotypes and improve vector potency, thus lowering the concentration of rAAV particle required to achieve the desired effect. Further disclosed herein are buffers for storage and manufacturing of rAAV particles comprising PVA.

Nucleic acid constructs and compositions that allow insertion and/or expression of a retinoschisin coding sequence are provided. Nuclease agents targeting RS1 loci are provided. Compositions and methods of using such constructs for integration into a target genomic locus and/or expression in a cell are also provided. Methods of treating X-linked juvenile retinoschisis using the nucleic acid constructs and compositions are also provided.

The present invention provides compositions and methods for treating a myopathy. In certain embodiments, the invention provides compositions and methods for treating, improving muscle function, and prolonging survival in a subject with X-linked myotubular myopathy (XLMTM). The present invention provides a method comprising systemic administration of a composition that induces the increased expression of myotubularin in the muscle of a subject. The invention provides sustained regional and global increases in muscle function.

The present application provides materials and methods for treating a patient with one or more condition associated with FXN whether ex vivo or in vivo. In addition, the present application provides materials and methods for editing and/or modulating the expression of FXN gene in a cell by genome editing.

The present invention provides, among other things, methods of treating Pompe disease, including administering to a subject in need of treatment a composition comprising an mRNA encoding acid alpha-glucosidase (GAA) at an effective dose and an administration interval such that at least one symptom or feature of Pompe disease is reduced in intensity, severity, or frequency or has delayed in onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.

The present invention provides a method for preventing or treating a liver disease selected from the group consisting of non-alcoholic fatty liver, non-alcoholic steatohepatitis and hepatic fibrosis comprising administrating at least one selected from the group consisting of an Ssu72 peptide, a polynucleotide encoding the Ssu72 peptide, and an expression vector comprising the polynucleotide.

A method for treating a subject having a medical condition associated with inflammation and/or an unwanted immune response without an alpha1-antitrypsin (AAT) deficiency, wherein the method comprises administering genetically modified mesenchymal stem cells to the subject, wherein said genetically modified mesenchymal stem cells comprise an exogenous nucleic acid comprising (i) an Alpha-1 antitrypsin (AAT) encoding region operably linked to (ii) a promoter or promoter/enhancer combination.

Nucleic acid regulatory elements that are able to enhance muscle-specific expression of genes, in particular expression in muscle cells and/or tissues such as in diaphragm, smooth muscle, heart and/or skeletal muscle, including at least two diaphragm-specific regulatory elements and a heart- and skeletal muscle-specific regulatory element. Expression cassettes and vectors containing these nucleic acid regulatory elements, as well as uses thereof such as applications using gene therapy of muscle-related disorders, more particularly diaphragm, heart and/or skeletal muscle-directed gene therapy, and for vaccination purposes.

The present invention provides novel viral vectors for use in human therapy, particularly for use in in the treatment of a disease or disorder which has its origin in the brain or is brain based, particularly a PGRN-associated neurodegenerative disease or disorder including frontotemporal degenerative disease or disorder such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. The invention also provides viral vectors for use in the treatment of brain tumors, particularly brain tumors selected from the group consisting of glioblastoma, glioma, ganglioneuroblastoma, astrocytoma, oligodendroglioma, PNET (primitive neuroectodermal), medulloblastoma, CNS lymphoma, and neuroblastoma, or any other CNS tumor and further in the treatment of brain metastasis, originating from any forms of breast, lung, colon, testicular, renal carcinomas and melanoma, or any other solid tumor, and any hematologic tumor, comprising all forms of leukemia and lymphomas. Further, the viral vectors may be used in the treatment of autoimmune diseases, inflammatory diseases and/or allergic diseases.