Gene therapies for lysosomal disorders
Inventors
Abeliovich, Asa • Heckman, Laura • RHINN, Herve
Assignees
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Publication Number
US-11655460-B2
Publication Date
2023-05-23
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 disclosure describes gene-therapy expression constructs for lysosomal disorders linked to Parkinson’s disease (PD), including Gaucher disease. The constructs are designed to deliver lysosome/trafficking-related genes, including Progranulin (PGRN), as well as other lysosomal genes mentioned in the disclosure, with the goal of restoring lysosomal function relevant to PD/LBD/Gaucher patients by expressing lysosome-associated proteins.
The disclosed expression constructs include promoter elements operably linked to transgene inserts encoding lysosome/trafficking-related proteins, with the transgene insert sequence specified using sequence identifiers. The disclosure further specifies regulatory architectures for viral vector expression, including AAV inverted terminal repeat (ITR) configurations used in connection with baculovirus vectors and named promoter and regulatory elements, as well as enhancer and polyA tail elements.
The disclosure provides rationale and experimental context for the constructs in lysosomal disorder models connected to PD, including chemical and genetic mouse models. It describes assessment of lysosomal enzyme activity and substrate-related readouts, along with behavioral endpoints and biodistribution/toxicity evaluations. The overall concept is a gene-therapy approach using baculovirus vector expression constructs to deliver PGRN and other lysosomal-related genes to support lysosomal function in disease-relevant settings.
Claims Coverage
The provided independent claims are clm-00001 and clm-00014, and the claim set shown includes 2 inventive features across these independents.
Baculovirus vector for PGRN with sequence-defined transgene insert
A Baculovirus vector comprising a nucleic acid comprising an expression construct comprising a promoter operably linked to a transgene insert encoding a Progranulin (PGRN) protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 68.
Ordered baculovirus construct with ITRs, CMV enhancer, CBA promoter, WPRE, and bGH polyA tail
A Baculovirus vector comprising a nucleic acid comprising, in 5′ to 3′ order: a first ITR; a CMV enhancer; a CBA promoter; a transgene insert encoding a PGRN protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 68; a WPRE; a Bovine Growth Hormone polyA signal tail; and a second ITR.
Across the provided independent claims, the inventive coverage centers on baculovirus vector expression constructs that drive Progranulin (PGRN) protein expression using a promoter operably linked to a transgene insert defined by the nucleotide sequence of SEQ ID NO: 68, and a specific 5′ to 3′ ordered arrangement of regulatory and ITR elements including CMV enhancer, CBA promoter, WPRE, and bovine growth hormone polyA signal tail.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Gene-therapy expression constructs for lysosomal disorders linked to Parkinson’s disease (PD), including Gaucher disease.
Assessment in chemical CBE mouse model and genetic 4L/PS-NA mouse model, including measurements related to lysosomal enzyme activity and disease-relevant endpoints.
Potential clinical trial contexts for PD/LBD/Gaucher patients [procedural detail omitted for safety].
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