Gene therapies for lysosomal disorders
Inventors
Abeliovich, Asa • Heckman, Laura • RHINN, Herve • WONG, Li Chin • LIN, Hsuan-Ni • HEFTI, Franz
Assignees
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Publication Number
US-11999974-B2
Publication Date
2024-06-04
Expiration Date
Abstract
The disclosure relates to compositions and methods for treatment of diseases associated with aberrant lysosomal function, such as fronto-temporal dementia (FTD). The disclosure also provides expression constructs comprising a transgene encoding progranulin or a portion thereof. The disclosure provides methods of treating FTD by administering such expression constructs to a subject in need thereof.
Core Innovation
The invention relates to a gene-therapy platform for treating a subject having fronto-temporal dementia with a GRN mutation by administering a recombinant adeno-associated virus (rAAV). The rAAV comprises a rAAV vector with an expression construct that encodes a progranulin (PGRN) protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 68, and the rAAV vector includes promoter and expression construct elements configured to drive PGRN expression and is packaged with an AAV9 capsid protein.
The administration is performed by an injection into the cisterna magna. In the described vector organization, the expression construct includes AAV2 inverted terminal repeats (ITR), a CMV enhancer, a CBA promoter, a WPRE element, and a bovine growth hormone polyA signal tail, together with the transgene insert encoding PGRN and an AAV9 capsid protein.
The described platform targets lysosomal and CNS dysfunction associated with GRN mutation and emphasizes restoration of PGRN-associated biology. In iPSC-derived FTD-GRN neuronal cultures and Grn KO aged and adult mouse studies, the platform is reported to show dose-dependent PGRN expression, restored cathepsin D maturation, reversal of TDP-43 pathology, increased human PGRN expression, reduced lipofuscin and ubiquitin accumulation, and suppression of neuroinflammatory markers.
Claims Coverage
The provided material includes two independent claims, both directed to treating a subject with fronto-temporal dementia with a GRN mutation using an rAAV delivered into the cisterna magna. Across the two independent claims, there are 2 main inventive-feature groupings: an rAAV vector with a promoter operably linked to a PGRN transgene (SEQ ID NO:68) packaged in an AAV9 capsid for cisterna magna injection, and a specified 5′ to 3′ AAV2/CMV/CBA/WPRE/bGH-polyA/AAV2 ITR expression construct organization for the same PGRN transgene, also packaged in an AAV9 capsid and administered into the cisterna magna.
Cisterna magna delivery of AAV9-packaged PGRN transgene under a promoter
A method for treating a subject having fronto-temporal dementia with a GRN mutation by administering an rAAV comprising a rAAV vector with 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, and an AAV9 capsid protein; wherein the rAAV is administered via an injection into the cisterna magna.
Defined 5′ to 3′ AAV2/CMV/CBA/WPRE/bGH polyA/AAV2 expression construct organization with AAV9 capsid for cisterna magna injection
A method for treating a subject having fronto-temporal dementia with a GRN mutation by administering an rAAV comprising a rAAV vector comprising, in 5′ to 3′ order, an AAV2 ITR, a CMV enhancer, a CBA promoter, a transgene insert encoding a PGRN protein with the nucleotide sequence of SEQ ID NO: 68, a WPRE, a Bovine Growth Hormone polyA signal tail, and an AAV2 ITR, and an AAV9 capsid protein; wherein the rAAV is administered via an injection into the cisterna magna.
Both independent claims cover cisterna magna injection of an rAAV packaged in an AAV9 capsid to express PGRN from a SEQ ID NO:68 transgene. The second independent claim further specifies a particular ordered vector genome organization incorporating AAV2 ITRs, CMV enhancer, CBA promoter, WPRE, and bovine growth hormone polyA signal tail.
Stated Advantages
Dose-dependent secreted progranulin restoration in FTD-GRN neurons after PR006A transduction.
Rescue of cathepsin D maturation, including a matCTSD/proCTSD ratio improvement.
Reversal of TDP-43 pathology, including reduced insoluble TDP-43 and increased nuclear localization.
Increased human progranulin and broad CNS and peripheral vector biodistribution after ICV PR006A in aged and adult Grn knockout mice.
Reduction of lipofuscin and ubiquitin accumulation.
Suppression of neuroinflammation, including TNFα/CD68 and microgliosis (Iba1).
No PR006A-related adverse findings in histopathology within the disclosed assessment context.
Documented Applications
Nonclinical characterization and efficacy of PR006A (rAAV expressing human PGRN) in FTD-GRN models, including iPSC-derived NSCs/neurons and Grn knockout mice.
Translational assessment using a non-human primate GLP framework including dosing assessment, biodistribution/transgene expression, immunogenicity, and CSF biomarker quantification of progranulin using automated Simple Western™ (Jess).
Intended Phase 1/2 open-label human clinical trial using CSF biomarkers (progranulin and NfL), volumetric MRI, and clinical endpoints including CDR plus NACC FTLD.
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