Gene therapy for neurodegenerative disorders
Inventors
Abeliovich, Asa • Heckman, Laura • RHINN, Herve
Assignees
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Publication Number
US-12049626-B2
Publication Date
2024-07-30
Expiration Date
Abstract
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.
Core Innovation
The invention relates to gene therapy for Parkinson’s disease and related neurodegenerative disorders, including Lewy Body Dementia (LBD), with emphasis on patients with Gaucher disease who are at increased risk for Parkinson’s disease and/or LBD. The therapy uses expression constructs that include a lysosomal enzyme (Gcase/GBA1 or fragments) together with inhibitory RNAs targeting PD-associated genes.
The inhibitory RNA component is described as one or more microRNA, shRNA, amiRNA, siRNA, or dsRNA, where the nucleic acid encodes inhibitory RNA molecules having complementarity to PD-associated genes. Documented targets include α-Synuclein (SNCA/α-Syn), TMEM106B, RPS25, and MAPT.
A key construct design described is an expression cassette architecture flanked by adeno-associated virus inverted terminal repeats (ITRs). The architecture includes promoters such as CBA/CAG/JeT and transcriptional elements such as U6-type Pol III, and it also includes IRES or self-cleaving peptides such as T2A between gene products.
The document further describes an AAV ITR design advantage involving a modified “D” region position on the outside to enable efficient encapsidation/transduction and to reduce toxicity, with options including truncated/ΔITR and modified “D” region placement with a “TRY region.”
Claims Coverage
The provided material includes two independent claims. Each independent claim focuses on miRNA transgenes directed to MAPT via SEQ ID NOs: 46-61 and short complementarity regions, packaged as an expression construct flanked by AAV ITRs, including a defined regulatory cassette order in the rAAV vector context.
MAPT-complementary miRNA isolated nucleic acid flanked by AAV ITRs
An isolated nucleic acid comprising an expression construct with a transgene encoding one or more microRNA including a region of complementarity to the microtubule-associated protein tau (MAPT) gene, where the one or more miRNA is encoded by SEQ ID NOs: 46-61 and the region of complementarity is between 6 and 30 nucleotides, wherein two adeno-associated virus inverted terminal repeat sequences flank the expression construct.
Ordered rAAV vector encoding MAPT-complementary miRNA transgene with regulatory cassette elements and flanking ITRs
A recombinant adeno-associated virus vector comprising a nucleic acid in 5’ to 3’ order including a 5’ AAV inverted terminal repeat, a CMV enhancer, a CBA promoter, a transgene encoding one or more miRNA with a region of complementarity to the MAPT gene encoded by SEQ ID NOs: 46-61 and where the complementarity region is between 6 and 30 nucleotides, a WPRE, a BGH polyA signal tail, and a 3’ AAV ITR.
Across the independent claims, the inventive coverage centers on miRNA transgenes directed to MAPT via SEQ ID NOs: 46-61 and short complementarity regions, packaged as an expression construct flanked by AAV ITRs, including a defined regulatory cassette order in the rAAV vector context.
Stated Advantages
Efficient encapsidation/transduction enabled by a modified “D” region position on the outside.
Reduced toxicity associated with the modified “D” region design.
Documented Applications
Gene therapy context for Parkinson’s disease and related neurodegenerative disorders, particularly for Gaucher disease patients at increased PD/LBD risk.
In vitro testing context including HEK293 assays for PD-associated gene silencing and transduction impact related to ITR D-position.
In vivo testing context including mutant mouse and chemical Gaucher models assessing CNS/CSF substrate and Gcase activity/endpoints.
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