Gene therapies for lysosomal disorders
Inventors
Abeliovich, Asa • Heckman, Laura • RHINN, Herve
Assignees
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Publication Number
US-11060113-B2
Publication Date
2021-07-13
Expiration Date
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 and Gaucher disease. In some embodiments, the disclosure provides expression constructs comprising a transgene encoding beta-Glucocerebrosidase (GBA) or a portion thereof, Lysosomal Membrane Protein 2 (LIMP2), Prosaposin, 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.
Core Innovation
The invention relates to gene-therapy approaches for Parkinson’s disease characterized by a mutation in a GBA1 gene in a subject, using recombinant adeno-associated virus (rAAV) administered directly to the central nervous system. The rAAV comprises an AAV9 capsid protein and an rAAV vector that mediates treatment of the Parkinson’s disease characterized by the mutation in the GBA1 gene.
The rAAV vector includes an expression construct with a promoter operably linked to a transgene insert encoding a Gcase protein. The transgene insert comprises the nucleotide sequence of SEQ ID NO: 15, described as a codon optimized version of the wild type GBA1 nucleotide sequence that eliminates a predicted donor splice site beginning at nucleotide 49.
The described rAAV architectures further specify nucleic-acid arrangement and regulatory elements, including a 5′ AAV ITR, a CMV enhancer, a CBA promoter, a transgene insert encoding the Gcase protein (SEQ ID NO: 15), a WPRE, a bovine growth hormone polyA signal tail, and a 3′ AAV ITR. The invention also frames an objective of increasing activity of a Gcase protein in a subject with Parkinson’s disease characterized by a GBA1 mutation.
Claims Coverage
The provided material includes three independent claims. Collectively, they cover CNS administration of an AAV9-capsid rAAV expressing a codon-optimized Gcase transgene (SEQ ID NO: 15) and, in one claim, a specific ordered nucleic-acid architecture of the expression construct, including defined regulatory elements and flanking ITRs.
AAV9 rAAV CNS treatment with codon-optimized Gcase transgene
A method for treating Parkinson’s disease characterized by a mutation in a GBA1 gene in a subject, comprising administering directly to the central nervous system an rAAV comprising an AAV9 capsid protein and a rAAV vector with an expression construct comprising a promoter operably linked to a transgene insert encoding a Gcase protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 15, and wherein the rAAV vector comprises two adeno-associated virus ITR sequences flanking the expression construct.
Ordered CMV/CBA/WPRE/Growth Hormone polyA construct flanked by AAV ITRs
A method for treating Parkinson’s disease characterized by a mutation in a GBA1 gene in a subject, comprising administering directly to the central nervous system an rAAV comprising an AAV9 capsid protein and a rAAV vector comprising a nucleic acid comprising, in 5′ to 3′ order: a 5′ AAV ITR; a CMV enhancer; a CBA promoter; a transgene insert encoding a Gcase protein with the nucleotide sequence of SEQ ID NO: 15; a WPRE; a bovine growth hormone polyA signal tail; and a 3′ AAV ITR.
Increasing Gcase activity using codon-optimized SEQ ID NO: 15 AAV9 rAAV
A method for increasing activity of a Gcase protein in a subject with Parkinson’s disease characterized by a mutation in a GBA1 gene, comprising administering directly to the central nervous system an rAAV comprising an AAV9 capsid protein and a rAAV vector with an expression construct comprising a promoter operably linked to a transgene insert encoding the Gcase protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 15, and wherein the rAAV vector comprises two adeno-associated virus ITR sequences flanking the expression construct.
Across the independent claims, the coverage centers on rAAV-mediated modulation of GBA1/Gcase in Parkinson’s disease with a GBA1 mutation by direct central nervous system administration using an AAV9 capsid, and a vector carrying SEQ ID NO: 15 encoding a codon-optimized Gcase transgene, with regulatory elements and ITR flanking sequences defined in at least one ordered-construct claim.
Stated Advantages
Mediating the treatment of Parkinson’s disease characterized by a mutation in a GBA1 gene in the subject.
Mediating the increase in the activity in the Gcase protein in the subject with Parkinson’s disease characterized by the mutation in the GBA1 gene.
Documented Applications
Treating Parkinson’s disease characterized by a mutation in a GBA1 gene by administering an AAV9 rAAV directly to the central nervous system.
Increasing activity of a Gcase protein in a subject with Parkinson’s disease characterized by a mutation in a GBA1 gene by administering an AAV9 rAAV directly to the central nervous system.
CNS-directed delivery using intra-cisterna magna injection is described in dependent claim material.
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