Gene therapies for lysosomal disorders
Inventors
Abeliovich, Asa • Heckman, Laura • RHINN, Herve
Assignees
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Publication Number
US-11993790-B2
Publication Date
2024-05-28
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 (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 disclosed subject matter relates to lysosomal disorders and neurodegenerative disease treatment using isolated nucleic acids and adeno-associated virus (AAV) expression constructs encoding lysosomal- or disease-associated proteins. In particular, the nucleic acid constructs include a transgene encoding a TREM2 protein, wherein the TREM2 protein is encoded by the nucleic acid sequence set forth in SEQ ID NO: 58. The transgene is flanked by two AAV inverted terminal repeat (ITR) sequences, forming an expression construct for AAV-mediated delivery.
The approach further characterizes recombinant AAV (rAAV) vectors by defining regulatory and functional elements arranged in a 5′ to 3′ order, including a cytomegalovirus (CMV) enhancer, a chicken beta-actin (CBA) promoter, a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE), and a bovine growth hormone polyA signal tail, together with 5′ and 3′ AAV ITRs. The disclosed embodiments also include rAAV vectors that specify an AAV capsid protein and, in some examples, narrow the capsid identity to AAV9. The document also describes cellular and nucleic-acid embodiments used to provide the claimed expression cassette and vector components.
The document connects these genetic constructs to treating Alzheimer’s disease and related subject populations through CNS delivery concepts and other administration concepts. The disclosed administration contexts include direct injection into a subject’s CNS, including intracerebral, intraparenchymal, intrathecal, and intra-cisterna magna (ICM) injection, with related discussion of CNS delivery. Additionally, the broader disclosure frames gene-therapy strategies for lysosomal disorders such as Gaucher disease and Parkinson’s disease, including optional combination with inhibitory nucleic acids targeting alpha-synuclein (SNCA/SCNA) and/or TMEM106B.
Claims Coverage
The partial claims provided include three independent claims (clm-00001, clm-00004, clm-00009). Across these independent claims, the coverage is centered on an isolated nucleic acid and corresponding rAAV vectors carrying a TREM2 transgene encoded by SEQ ID NO: 58 and flanked/assembled with AAV ITRs, together with defined expression-control elements and, in some embodiments, an AAV capsid protein for delivery.
Isolated nucleic acid with TREM2 transgene flanked by AAV ITRs
An isolated nucleic acid comprising an expression construct with a transgene encoding a TREM2 protein, wherein the TREM2 protein is encoded by the nucleic acid sequence in SEQ ID NO: 58, and two adeno-associated virus (AAV) inverted terminal repeat (ITR) sequences flanking the expression construct.
Recombinant rAAV vector with TREM2 transgene flanked by AAV ITRs
A recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid including an expression construct with a transgene encoding a TREM2 protein flanked by two AAV inverted terminal repeats (ITRs), wherein the TREM2 protein is encoded by the nucleic acid sequence set forth in SEQ ID NO: 58.
Ordered rAAV vector regulatory cassette with CMV enhancer, CBA promoter, WPRE, and bovine growth hormone polyA
A recombinant adeno-associated virus (AAV)(rAAV) vector comprising a nucleic acid in 5′ to 3′ order consisting of a 5′ AAV ITR, a CMV enhancer, a CBA promoter, a transgene encoding a TREM2 protein encoded by SEQ ID NO: 58, a WPRE, a bovine growth hormone polyA signal tail, and a 3′ AAV ITR.
Taken together, the independent claims cover a TREM2-encoding nucleic acid cassette and matched rAAV vector formats, with flanking AAV ITR sequences and defined expression-control elements (including CMV enhancer, CBA promoter, WPRE, and bovine growth hormone polyA) in a specified order. Some embodiments further define an AAV capsid protein, including AAV9, and additional dependents address administration contexts in Alzheimer’s disease and CNS-directed delivery.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of Alzheimer’s disease in a subject (including treatment via direct CNS injection such as intracerebral, intraparenchymal, intrathecal, or intra-cisterna magna (ICM) injection).
Gene-therapy strategies for lysosomal disorders, including Gaucher disease and Parkinson’s disease (PD), and related populations such as Lewy Body Dementia (LBD).
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