Gene therapies for lysosomal disorders
AssigneePrevail Therapeutics, Inc.
InventorsAsa ABELIOVICH, Laura HECKMAN, Herve RHINN
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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.
Claims27
-43. (canceled)
An isolated nucleic acid comprising:
- (i) 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, which is a codon optimized version of wild type GBA1 nucleotide sequence, wherein the codon optimized sequence eliminates a predicted donor splice site that begins at nucleotide 49 in the wild type GBA1 nucleotide sequence;
- and
- (ii) two adeno-associated virus (AAV) inverted terminal repeat (ITR) sequences flanking the expression construct.
An isolated nucleic acid comprising, in 5′ to 3′ order:
- (a) a 5′ AAV ITR;
- (b) a CMV enhancer;
- (c) a CBA promoter;
- (d) a transgene insert encoding a Gcase protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO:
- 15;
- (e) a WPRE;
- (f) a Bovine Growth Hormone polyA signal tail;
- and
- (g) a 3′ AAV ITR.
A plasmid comprising a nucleic acid comprising:
- (i) 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, which is a codon optimized version of wild type GBA1 nucleotide sequence, wherein the codon optimized sequence eliminates a predicted donor splice site that begins at nucleotide 49 in the wild type GBA1 nucleotide sequence;
- and
- (ii) two AAV ITR sequences flanking the expression construct.
A Baculovirus vector comprising a nucleic acid comprising:
- (i) 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, which is a codon optimized version of wild type GBA1 nucleotide sequence, wherein the codon optimized sequence eliminates a predicted donor splice site that begins at nucleotide 49 in the wild type GBA1 nucleotide sequence;
- and
- (ii) two AAV ITR sequences flanking the expression construct.
A cell comprising:
- (i) a first vector encoding one or more adeno-associated virus rep proteins and/or one or more adeno-associated virus cap proteins;
- and
- (ii) a second vector comprising a nucleic acid comprising:
- (a) 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, which is a codon optimized version of wild type GBA1 nucleotide sequence, wherein the codon optimized sequence eliminates a predicted donor splice site that begins at nucleotide 49 in the wild type GBA1 nucleotide sequence;
- and
- (b) two AAV ITR sequences flanking the expression construct.
A method for treating Gaucher disease in a subject, the method comprising administering to the subject a rAAV comprising:
- (i) an AAV9 capsid protein;
- and
- (ii) a rAAV vector comprising a nucleic acid comprising 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, which is a codon optimized version of the wild type GBA1 nucleotide sequence, wherein the codon optimized sequence eliminates a predicted donor splice site that begins at nucleotide 49 in the wild type GBA1 nucleotide sequence, and wherein the rAAV vector comprises two adeno-associated virus inverted terminal repeats (ITR) sequences flanking the expression construct;
- thereby mediating the treatment of the Gaucher disease in the subject.
Dependencies are inferred from the claim text.