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-12516298-B2
Publication Date
2026-01-06
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 pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) vector that delivers a transgene insert encoding a progranulin (PGRN) protein. The transgene insert comprises the nucleotide sequence of SEQ ID NO: 68, and the nucleic acid expression construct includes a promoter operably linked to the transgene insert encoding PGRN. The rAAV vector is associated with an adeno-associated virus (AAV) 9 capsid protein.
The rAAV expression construct includes regulatory elements and sequence components described in the claim set, including a chicken beta actin (CBA) promoter, a cytomegalovirus (CMV) enhancer, a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE), bovine growth hormone polyA signal tail, and adeno-associated virus inverted terminal repeats (ITRs). In certain embodiments, the construct includes a TRY region containing SEQ ID NO: 28.
The pharmaceutical composition is formulated in a buffer/vehicle containing about 20 mM Tris, pH 8.0, about 1 mM MgCl2, about 200 mM NaCl, and about 0.001% w/v poloxamer 188. The disclosed subject matter is positioned for lysosomal/FTD-GRN disease contexts in the provided document summary, centering on delivering progranulin (PGRN/GRN) via an AAV9-capsid rAAV vector.
Claims Coverage
The partial content provides two independent claims. Each independent claim centers on an rAAV pharmaceutical composition that encodes PGRN using a defined SEQ ID NO: 68 transgene and an AAV9 capsid, with one claim additionally specifying a particular 5′ to 3′ order of multiple regulatory elements and sequence components within the vector nucleic acid.
AAV9-capsid rAAV encoding PGRN from SEQ ID NO: 68 with promoter-linked expression construct
A pharmaceutical composition comprising an rAAV vector with a nucleic acid expression construct including 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 wherein the rAAV vector is associated with an AAV 9 capsid protein.
Defined formulation buffer containing Tris, MgCl2, NaCl, and poloxamer 188
The pharmaceutical composition further comprises about 20 mM Tris, pH 8.0, about 1 mM MgCl2, about 200 mM NaCl, and about 0.001% w/v poloxamer 188.
Vector nucleic-acid component order with AAV2 ITRs and PGRN elements
A pharmaceutical composition comprising an rAAV vector in 5′ to 3′ order including an AAV2 inverted terminal repeat (ITR), a cytomegalovirus (CMV) enhancer, a chicken beta actin (CBA) promoter, a transgene insert encoding a progranulin (PGRN) protein comprising the nucleotide sequence of SEQ ID NO: 68, a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE), a bovine growth hormone polyA signal tail, and an AAV2 ITR; together with an AAV9 capsid protein.
Overall, the independent claims cover a pharmaceutical composition that uses an AAV9-capsid rAAV to deliver a PGRN transgene containing SEQ ID NO: 68 under a promoter-linked expression construct, and a defined formulation buffer. One independent claim further limits the vector by requiring a specific 5′ to 3′ order of regulatory elements including CMV enhancer, CBA promoter, WPRE, and a bovine growth hormone polyA signal tail flanked by AAV2 ITRs.
Stated Advantages
Restores secreted progranulin in a dose-dependent manner in iPSC-derived NSC/neuronal models.
Rescues cathepsin D maturation (proCTSD→matCTSD).
Normalizes TDP-43 pathology, including reduced insoluble TDP-43 and increased nuclear localization.
In Grn knockout mice, yields broad vector genome distribution and increases human progranulin in CNS and peripheral tissues.
Reduces lipofuscin/ubiquitin accumulation.
Suppresses neuroinflammation markers, including TNFα and CD68, and reduces microgliosis (Iba1) and some astrocytosis.
Shows no PR006A-related adverse findings in the described toxicity/biodistribution study.
Detects vector presence and transgene expression in CNS and peripheral tissues, including CSF progranulin detection.
In the described GLP NHP study, shows no clinical/ECG adverse effects.
Documented Applications
Nonclinical efficacy application to FTD-GRN settings using iPSC-derived NSC/neuronal models with GRN mutation and heterozygous GRN mutant lines.
Nonclinical efficacy application in aged and adult Grn KO mouse models using ICV administration.
Nonclinical biodistribution and toxicity/biodistribution application in a GLP NHP single-dose ICM study, with detection of vector presence and human progranulin in CNS/peripheral tissues and CSF.
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