Gene therapies for lysosomal disorders

Inventors

Abeliovich, Asa • Heckman, Laura • RHINN, Herve

Assignees

Prevail Therapeutics Inc

Abstract

The disclosure relates, in some aspects, to compositions and methods for treatment of diseases associated with aberrant lysosomal function, for example Parkinson's disease (PD) and Gaucher disease. In some embodiments, the disclosure provides expression constructs comprising a transgene encoding beta-Glucocerebrosidase (GBA) or a portion thereof alone or in combination with one or more PD-associated genes. In some embodiments, the disclosure provides methods of Parkinson's disease by administering such expression constructs to a subject in need thereof.

Core Innovation

The invention relates to gene therapy compositions for lysosomal disorders, with emphasis on Parkinson’s disease (PD) and Gaucher disease, using expression constructs delivered as isolated nucleic acids or recombinant adeno-associated virus (rAAV) vectors. The compositions are configured to express prosaposin (PSAP), where the PSAP protein is encoded by the nucleic acid sequence in SEQ ID NO: 17, and the expression construct is flanked by two adeno-associated virus (AAV) inverted terminal repeat (ITR) sequences.

The invention addresses a lysosomal intervention strategy by providing nucleic-acid-based delivery of lysosomal/trafficking genes, described as expressed alone or in combination for PD/lysosomal intervention. The document further describes inhibitory nucleic acids targeting α-synuclein (SNCA/SCNA) and/or TMEM106B as optional components in the broader PD/lysosomal approach, and it frames delivery through CNS-direct or peripheral injection concepts.

For rAAV implementation, the document describes AAV vector architectures that include promoter and regulatory elements and AAV ITRs, and it specifies recombinant rAAV vector designs in terms of nucleic-acid order and defined components such as CMV enhancer, chicken beta-actin (CBA) promoter, Woodchuck hepatitis virus Posttranscriptional Regulatory Element (WPRE), and a bovine growth hormone polyA (bGH polyA) signal tail, together with AAV ITRs. It also describes selected AAV capsid options, including AAV9, and describes experimental framing involving PSAP and lysosomal readouts and encapsidation/transduction considerations for modified ITR region placement.

Claims Coverage

The partial content includes three independent claims that share a common inventive concept: an isolated nucleic acid or an rAAV vector carrying a PSAP transgene encoded by SEQ ID NO: 17, with the expression construct flanked by two AAV ITRs, and in one claim further defined by specific regulatory elements and sequence order within an rAAV cassette.

Across the independent claims, the inventive coverage centers on PSAP (SEQ ID NO: 17) delivered via an expression construct flanked by two AAV ITRs, with one independent claim further specifying a defined rAAV cassette composition and 5′ to 3′ order including CMV enhancer, CBA promoter, WPRE, and bGH polyA.

Stated Advantages

Documented Applications