Recombinant adeno-associated virus for treatment of GRN-associated adult-onset neurodegeneration

Inventors

Wilson, James M. • Hinderer, Christian • Miller, Nimrod

Assignees

University of Pennsylvania Penn

Abstract

A recombinant AAV (rAAV) suitable for use in treating adult onset neurodegeneration caused by granulin (GRN) haploinsufficiency, such as progranulin (PGRN)-related frontotemporal dementia (FTD), is provided. The rAAV comprises (a) an adeno-associated virus 1 capsid, and (b) a vector genome packaged in the AAV capsid, said vector genome comprising AAV inverted terminal repeats, a coding sequence for human progranulin, and regulatory sequences which direct expression of the progranulin. Also provided are a method for treating a human patient with PGRN-FTD and other adult onset neurodegeneration caused by granulin (GRN) haploinsufficiencies, comprising delivering to the central nervous system (CNS) a recombinant adeno-associated virus (rAAV) having an adeno-associated virus 1 (AAV1) capsid, said rAAV further comprising a vector genome packaged in the AAV capsid, said vector genome comprising AAV inverted terminal repeats, a coding sequence for human progranulin, and regulatory sequences which direct expression of the progranulin.

Core Innovation

A recombinant AAV (rAAV) suitable for use in treating adult onset neurodegeneration caused by granulin (GRN) haploinsufficiency is provided, the rAAV comprising an adeno-associated virus 1 capsid and a vector genome packaged in the AAV capsid, said vector genome comprising AAV inverted terminal repeats, a coding sequence for human progranulin, and regulatory sequences which direct expression of the progranulin. A pharmaceutical composition comprising an aqueous liquid and a recombinant AAV (rAAV) is also provided, and in certain embodiments the aqueous liquid comprises an artificial cerebrospinal fluid with a surfactant. A method of treating a human patient with progranulin-related frontotemporal dementia (FTD) neurodegeneration or another adult onset neurodegeneration disease caused by GRN haploinsufficiency is provided, the method comprising delivering a rAAV including a human progranulin coding sequence to the central nervous system (CNS).

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease that typically presents in the sixth or seventh decade of life with deficits in executive function, behavior, speech, or language comprehension and is associated with a characteristic pattern of brain atrophy; in 5-10% of FTD patients pathogenic loss-of-function mutations can be identified in the granulin (GRN) gene encoding progranulin (PGRN). There are currently no disease modifying therapies for adult-onset neurodegeneration caused by GRN haploinsufficiency and that disease spectrum represents an area of high unmet medical need. What are needed are treatments for adult-onset neurodegenerative disorders associated with GRN haploinsufficiencies, and for the symptoms associated therewith.

In certain embodiments the rAAV comprises an AAV1 capsid and a vector genome comprising AAV ITRs, a human PGRN coding sequence and regulatory elements which direct its expression, and in certain embodiments the rAAV1.hPGRN targets ependymal cells and results in expression of secretable human progranulin. The compositions and methods include a pharmaceutical formulation suitable for [procedural detail omitted for safety] and embodiments further contemplate monitoring treatment by non-invasive assessment of retinal storage lesions as a predictor of reduction of brain lesions, magnetic resonance imaging to assess brain volume, and measuring progranulin concentration in the CSF.

Claims Coverage

Three inventive features were identified from the independent claims.

The independent claims principally cover (1) an rAAV having an AAV1 capsid and a vector genome encoding human progranulin (SEQ ID NO:3 or ≥95% identical), (2) a pharmaceutical composition containing such rAAV in an aqueous formulation suitable for [procedural detail omitted for safety], and (3) a vector genome architecture comprising an enhancer, chicken beta-actin promoter, an intron, the hPGRN coding sequence, and a polyadenylation sequence.

Stated Advantages

Documented Applications