The invention in some aspects relates to recombinant adeno-associated viruses useful for targeting transgenes to CNS tissue, and compositions comprising the same, and methods of use thereof. In some aspects, the invention provides methods and compositions for treating CNS-related disorders.

The disclosure relates, in some aspects, to compositions and methods for treatment of diseases associated with aberrant lysosomal function, for example Parkinson's disease and Gaucher disease. In some embodiments, the disclosure provides expression constructs comprising a transgene encoding one or more inhibitory nucleic acids targeting SCNA or a portion thereof, TMEM106B or a portion thereof, or any combination of the foregoing. In some embodiments, the disclosure provides methods of Parkinson's disease by administering such expression constructs to a subject in need thereof.

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.

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 (AMD)), 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.

The present disclosure provides recombinant adeno-associated virus virions with variant capsid protein, where the recombinant AAV (rAAV) virions exhibit one or more of increased ability to cross neuronal cell barriers, increased infectivity of a neural stem cell, increased infectivity of a neuronal cell, and reduced susceptibility to antibody neutralization, compared to a control AAV, and where the rAAV virions comprise a heterologous nucleic acid. The present disclosure provides methods of delivering a gene product to a neural stem cell or a neuronal cell in an individual. The present disclosure also provides methods of modifying a target nucleic acid present in a neural stem cell or neuronal cell.

Compositions and methods for treating disorders affecting motor function, such as motor function affected by disease or injury to the brain and/or spinal cord, are disclosed.

The invention is directed to the field of gene therapy, i.e. gene delivery into target cells, tissue, organ and organism, and more particularly to gene delivery via viral vectors. The inventors showed that it is possible by chemical coupling to modulate the coupling of a ligand in the surface of the capsid of AAV, for example AAV2 and AAV3b. In particular, the present invention relates to a recombinant Adeno-Associated Virus (rAAV) vector particle having at least one primary amino group contained in the capsid proteins, chemically coupled with at least one ligand L, wherein coupling of said ligand L is implemented through a bond comprising a CSNH bond and an optionally substituted aromatic moiety. Particularly, the inventors tested the chemical coupling of mannose ligand on AAV2 for subretinally injection to rats. The present invention further relates to a method for chemically coupling an Adeno-Associated Virus (AAV) vector particle with at least one ligand L and to a Recombinant Adeno-Associated Virus (rAAV) vector particle obtained by said method as well as a pharmaceutical composition comprising it and their corresponding medical use.

The invention relates to peptides, polypeptides or proteins which specifically bind to cells of the brain and/or the spinal cord. The peptides, polypeptides or proteins can be part of a viral capsid, and they can be used for guiding a recombinant viral vector selectively to the brain and/or spinal cord after systemic administration to a subject, where it provides for a tissue-specific expression of one or more transgenes. The invention therefore also relates to a recombinant viral vector, preferably an AAV vector, comprising a capsid containing at least one of the peptides, polypeptides or proteins of the invention and at least one transgene which is packaged within the capsid. The viral vector is particularly suitable for the therapeutic treatment of a disease or functional disorder of the brain and/or the spinal cord. The invention further relates to cells and pharmaceutical compositions comprising the viral vector of the invention.

Described herein are methods and compositions for treating subjects with spinal muscular atrophy (SMA) using CRISPR editing of exon 7 and/or intron 7 of SMN2.

Compositions and methods for treating disorders affecting motor function, such as motor function affected by disease or injury to the brain and/or spinal cord, are disclosed.