The present invention relates to the use of a regulatory nucleic acid sequences that are able to regulate gene expression in eukaryotic cells and which are responsive to the unfolded protein response (UPR). There are disclosed regulatable introns and UPR-inducible promoters, which are able to regulate gene expression. There are also disclosed recombinant expression constructs comprising such regulatory nucleic acid sequences, whereby expression of the encoded expression product can be induced by invoking the unfolded protein response (UPR) in a eukaryotic cell containing the construct, methods of using such constructs and associated vectors, cells and suchlike.

Provided herein are improved gene therapy vectors and methods of use, in some embodiments, comprising sequences for improved expression and cellular targeting of a therapeutic protein.

Provided are compositions related to HSD17B13 variants, including isolated nucleic acids and proteins related to variants of HSD17B13, and cells comprising those nucleic acids and proteins. Also provided are methods related to HSD17B13 variants. Such methods include methods for modifying a cell through use of any combination of nuclease agents, exogenous donor sequences, transcriptional activators, transcriptional repressors, and expression vectors for expressing a recombinant HSD17B13 gene or a nucleic acid encoding an HSD17B13 protein. Also provided are therapeutic and prophylactic methods for treating a subject having or at risk of developing chronic liver disease.

Provided herein are Class 2 Type V CRISPR:gNA systems comprising Class 2 Type V CRISPR polypeptides (e.g. CasX), guide nucleic acids (gNA), and optionally donor template nucleic acids useful in the modification of a RHO gene. The systems are also useful for introduction into cells, for example eukaryotic cells having mutations in the rhodopsin protein. Also provided are methods of using such systems to modify cells having such mutations and utility in methods of treatment of a subject with a RHO-related disease, such as retinitis pigmentosa.

Disclosed are nucleic acid constructs comprising a nucleic acid sequence encoding a vitelliform macular dystrophy-2 (VMD2) promoter operably linked to a nucleic acid sequence encoding Rap1a. Disclosed are vectors comprising the nucleic acid constructs disclosed herein. Disclosed are compositions comprising the disclosed nucleic acid constructs or vectors. Also disclosed are methods of treating a subject having age-related macular degeneration comprising administering one or more of the disclosed nucleic acid constructs, vectors, or compositions to a subject in need thereof.

Aspects of the disclosure relate to compositions and methods for treating certain diseases associated with the presence of one or more premature stop codons in a gene, for example dominantly inherited diseases or recessively inherited diseases. In some embodiments, compositions comprise a vector (e.g., a viral vector, such as an rAAV vector) encoding one or more synthetic suppressor transfer RNAs (tRNAs) configured to read-through certain stop codons (e.g., premature stop codons). In some embodiments, the disclosure relates to methods for treating Hurler syndrome comprising administering such vectors to a subject.

The present disclosure generally relates to compositions and methods of use thereof for treating heart failure encompassing administering a composition of modified mRNA (modRNA) encoding for type 2 phosphatidylinositol-5-phosphate 4-kinase gamma (pip4k2c) to heart tissue of a subject in need thereof.

The present invention provides gene therapies for the treatment of Friedreich's ataxia. Specifically, the present invention provides a nucleic acid, cloning vector and transfer vector for the production of an adeno-associated virus (AAV) vector. The nucleic acid comprises (i) a nucleic acid sequence encoding frataxin, (ii) a phospho-glycerate-kinase (PGK) promoter, and (iii) a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). The present invention also provides a pharmaceutical composition which comprises the AAV vector or nucleic acid. Also, the AAV vector, nucleic acid or pharmaceutical composition can be used as a medicament, specifically as a medicament for the treatment of Friedreich's ataxia.

Provided herein are modified AAV capsid proteins, particles, nucleic acid vectors, and compositions thereof, as well as methods of their use.

Disclosed are compositions and methods for treating neurological diseases, disorders, and injuries in a subject in need thereof. Particularly disclosed are compositions and methods for treating neurological diseases, disorders, and injuries that are associated with upper motor neurons in a subject in need thereof in which methods expression of ubiquitin carboxyl hydrolase ligase 1 (UCHL1) is modulated in the subject, for example, via gene therapy being administered to the subject in order to express UCHL1 in upper motor neurons of the subject. Also disclosed are expression vectors comprising the UCHL1 promoter operably linked to a nucleic acid encoding a therapeutic gene product.