Methods of treatment of complement-mediated disorders, in particular disorders associated with over-activity of the complement C3b feedback cycle (for example, age-related macular degeneration (AMI)), using gene therapy is described. According to the methods, levels of complement Factor I are elevated by administration of a recombinant viral vector encoding Factor I such that a therapeutically effective amount of the encoded Factor I is expressed from the vector in the subject. Recombinant viral vectors encoding Factor I, recombinant virus particles encapsidating the vectors, and their use in the methods of treatment, is also described.

Described is hybrid viral vector comprising: a first virus such as bacteriophage T4; one or more second virus such as adeno-associated virus (AAV) attached to the first virus through cross-bridges, such as avidin-biotin cross-bridges; one or more DNA molecules packaged in the first virus; one or more nucleic acid molecules packaged in the second virus; and one or more proteins displayed on the surface of the first virus. Also described are methods of making and using such a hybrid viral vector.

The present disclosure provides adeno-associated virus (AAV) virions with altered capsid protein that binds heparan sulfate proteoglycans, where the AAV virions exhibit greater infectivity of retinal cells, altered tropism and/or the ability to bind and cross the inner limiting membrane following intravitreal injection. The present disclosure further provides methods of delivering a gene product to a retinal cell in an individual, and methods of treating ocular disease.

This Application is a continuation of international patent application serial number PCT/US2018/054223, filed Oct. 3, 2018, which claims the benefit under 35 U.S.C. ? 119(e) of U.S. Provisional Application Ser. No. 62/567,303, filed Oct. 3, 2017, entitled GENE THERAPIES FOR LYSOSOMAL DISORDERS, and 62/567,305, filed Oct. 3, 2017, entitled GENE THERAPIES FOR LYSOSOMAL DISORDERS, the entire contents of each of which are incorporated herein by reference.

The present invention relates to a recombinant adeno-associated viral (r AAV) vector comprising neuropeptide Y (NPY) coding sequence and neuropeptide Y2 receptor (NPY2R) coding sequence. The invention further relates to a AAV particle comprising said vector, wherein the vector is encapsulated by adeno-associated virus (AAV) capsid proteins. Also, a pharmaceutical composition comprising said AAV particle, for use in the prevention or treatment of a neurological disorder in mammals, such as epilepsy.

The presently disclosed subject matter provides compositions and methods for the expression of CRISPR guide RNAs using the H1 promoter. In particular, compositions and methods are provided for the use of the H1 promoter to express CRISPR guide RNA (gRNA) with altered specificity of the 5 nucleotide, as well as use of the H1 promoter sequence as a bidirectional promoter to express Cas9 nuclease and the gRNA simultaneously. Compositions and methods are also provided for the expression and regulation of gRNA expression in vivo through the use of RNA ribozymes and regulatable aptazymes.

Disclosed herein are methods and compositions for insertion of transgene sequences encoding proteins that is aberrantly expressed in disease or disorder such as a lysosomal storage disease.

The disclosure relates to compositions and methods for treatment of diseases associated with aberrant lysosomal function, such as fronto-temporal dementia (FTD). The disclosure also provides expression constructs comprising a transgene encoding progranulin or a portion thereof. The disclosure provides methods of treating FTD by administering such expression constructs to a subject in need thereof.

The present disclosure provides adeno-associated virus (AAV) virions with altered capsid protein that binds heparan sulfate proteoglycans, where the AAV virions exhibit greater infectivity of retinal cells, altered tropism and/or the ability to bind and cross the inner limiting membrane following intravitreal injection. The present disclosure further provides methods of delivering a gene product to a retinal cell in an individual, and methods of treating ocular disease.

Disclosed herein are methods and compositions for insertion of transgene sequences encoding proteins that is aberrantly expressed in disease or disorder such as a lysosomal storage disease.