Gene therapies for lysosomal disorders

Inventors

Abeliovich, Asa • Heckman, Laura • RHINN, Herve • HEFTI, Franz

Assignees

Prevail Therapeutics Inc

Abstract

The disclosure relates to compositions and methods for treatment of diseases associated with aberrant lysosomal function, such as Parkinson's disease and Gaucher disease. The disclosure provides expression constructs comprising a transgene encoding beta-glucocerebrosidase, an inhibitory RNA targeting alpha-Synuclein, or a combination of the foregoing. The disclosure further provides methods of treating Gaucher disease, Parkinson's disease or other synucleinopathies by administering such expression constructs to a subject in need thereof.

Core Innovation

The invention relates to treating subjects having Type 1 Gaucher disease, Type 2 Gaucher disease, Type 3 Gaucher disease, and Parkinson’s disease with a GBA1 mutation using a recombinant adeno-associated virus (rAAV) comprising a nucleic acid expression construct and an AAV9 capsid protein. The rAAV vector includes a promoter operably linked to a transgene insert encoding a glucocerebrosidase (Gcase) protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 15.

For Type 2 Gaucher disease and Type 3 Gaucher disease, the construct further specifies a nucleic acid arrangement in 5′ to 3′ order including AAV2 ITR, a CMV enhancer, a CBA promoter, the Gcase transgene insert comprising SEQ ID NO: 15, a WPRE, a bovine growth hormone polyA signal tail, and an AAV2 ITR, together with an AAV9 capsid protein. Administration is carried out within the same brain dose range and may be specified as suboccipital injection into the cisterna magna.

The invention also covers treatment of Type 1 Gaucher disease by administering an rAAV comprising a promoter linked to a Gcase transgene insert comprising SEQ ID NO: 15 and an AAV9 capsid protein, with claimed dose ranges and an optionally specified intravenous administration route. For Parkinson’s disease with a GBA1 mutation, the invention includes administering an rAAV with the SEQ ID NO: 15 Gcase transgene and an AAV9 capsid protein, and in related embodiments includes a defined AAV2 ITR–CMV enhancer–CBA promoter–Gcase transgene insert–WPRE–bovine growth hormone polyA signal tail–AAV2 ITR configuration administered at doses ranging from about 5×10^13 vg to about 5×10^14 vg.

Claims Coverage

The independent claims cover treatment of Type 1, Type 2, and Type 3 Gaucher disease and Parkinson’s disease with a GBA1 mutation using rAAV constructs that combine an AAV9 capsid with a Gcase transgene insert defined by SEQ ID NO: 15. Across the independent claims, the inventive coverage includes four core construct variants, with one claim family further specifying a defined expression cassette architecture.

Across the independent claims, the inventive concept centers on rAAV-mediated Gcase expression using a SEQ ID NO: 15 transgene and an AAV9 capsid, with additional claim coverage specifying a defined AAV2 ITR/CMV enhancer/CBA promoter/WPRE/bovine growth hormone polyA cassette architecture for Type 2/Type 3 Gaucher disease and for Parkinson’s disease with a GBA1 mutation. Independent claims also cover Type 1 Gaucher disease using the AAV9 capsid and SEQ ID NO: 15 Gcase transgene expression construct.

Stated Advantages

Documented Applications