# US 11,993,790 B2 · Gene therapies for lysosomal disorders

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- Number: US 11,993,790 B2
- Document ID: US11993790B2
- Status: Granted
- Kind: B2
- Application number: 16/753,322
- Filed: 2018-10-03
- Published: 2020-09-03
- Granted: 2024-05-28
- Earliest claimed: 2017-10-03
- Assignees: Prevail Therapeutics, Inc.
- Applicants: Prevail Therapeutics, Inc.
- Inventors: Asa Abeliovich; Laura Heckman; Herve Rhinn
- Web page: https://patentgrep.com/patent/US11993790B2

## CPC

- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 9/2402: {hydrolysing O- and S- glycosyl compounds (3.2.1)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 35/76: Viruses; Subviral particles; Bacteriophages
- A61K 35/761: Adenovirus
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 25/16: Anti-Parkinson drugs
- C07K 14/005: from viruses
- C07K 14/435: from animals; from humans
- C07K 14/47: from mammals
- C07K 14/61: Growth hormone [GH], i.e. somatotropin
- C07K 14/70503: {Immunoglobulin superfamily}
- A01K 2207/20: Animals treated with compounds which are neither proteins nor nucleic acids
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2227/105: Murine
- A01K 2267/0306: Animal model for genetic diseases
- A61K 39/23: Parvoviridae, e.g. feline panleukopenia virus
- C07H 21/04: with deoxyribosyl as saccharide radical
- C12N 15/86: Viral vectors
- C12N 15/8645: {Adeno-associated virus}
- C12N 2750/14121: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2750/14122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2830/48: regulating transport or export of RNA, e.g. RRE, PRE, WPRE, CTE
- C12N 2830/50: regulating RNA stability, not being an intron, e.g. poly A signal
- C12Y 302/01045: Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C12Y: ENZYMES

## 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.

## Claims

### Claim 1

An isolated nucleic acid comprising (i) an expression construct comprising a transgene encoding a TREM2 protein, wherein the TREM2 protein is encoded by the nucleic acid sequence in SEQ ID NO: 58; and (ii) two adeno-associated virus (AAV) inverted terminal repeat (ITR) sequences flanking the expression construct.

### Claim 2 (depends on 1)

The isolated nucleic acid of claim 1, wherein the transgene is operably linked to a promoter, optionally wherein the promoter comprises a chicken beta-actin (CBA) promoter.

### Claim 3 (depends on 1)

The isolated nucleic acid of claim 1, wherein each ITR sequence is a wild-type AAV2 ITR sequence.

### Claim 4

A recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid comprising an expression construct comprising a transgene encoding a TREM2 protein flanked by two adeno-associated virus (AAV) inverted terminal repeats (ITRs), wherein the TREM2 protein is encoded by the nucleic acid sequence set forth in SEQ ID NO: 58.

### Claim 5 (depends on 4)

The rAAV vector of claim 4, wherein the transgene is operably linked to a promoter, optionally wherein the promoter comprises a chicken beta-actin (CBA) promoter.

### Claim 6 (depends on 4)

The rAAV vector of claim 4, wherein each ITR sequence is a wild-type AAV2 ITR sequence.

### Claim 7 (depends on 4)

A recombinant adeno-associated virus (rAAV) comprising:
(i) an AAV capsid protein; and
(ii) the rAAV vector of claim 4.

### Claim 8 (depends on 7)

The rAAV of claim 7, wherein the AAV capsid protein is AAV9 capsid protein.

### Claim 9

A recombinant adeno-associated virus (AAV)(rAAV) vector comprising a nucleic acid comprising, in 5′ to 3′ order:
(a) a 5′ AAV inverted terminal repeat (ITR);
(b) a cytomegalovirus (CMV) enhancer;
(c) a chicken beta-actin (CBA) promoter;
(d) a transgene encoding a TREM2 protein, wherein the TREM2 protein is encoded by the nucleic acid sequence in SEQ ID NO: 58;
(e) a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE);
(f) a Bovine Growth Hormone polyA signal tail; and
(g) a 3′ AAV ITR.

### Claim 10 (depends on 9)

A recombinant adeno-associated virus (rAAV) comprising:
(i) an AAV capsid protein; and
(ii) the rAAV vector of claim 9.

### Claim 11 (depends on 10)

The rAAV of claim 10, wherein the AAV capsid protein is AAV9 capsid protein.

### Claim 12 (depends on 9)

A plasmid comprising the rAAV vector of claim 9.

### Claim 13 (depends on 1)

A Baculovirus vector comprising the isolated nucleic acid of claim 1.

### Claim 14 (depends on 1)

A cell comprising:
(i) a first vector encoding one or more AAV rep protein and/or one or more AAV cap protein; and
(ii) a second vector comprising the isolated nucleic acid of claim 1.

### Claim 15 (depends on 14)

The cell of claim 14, wherein the first vector is a plasmid and the second vector is a plasmid.

### Claim 16 (depends on 14)

The cell of claim 14, wherein the first vector is a Baculovirus vector and the second vector is a Baculovirus vector.

### Claim 17 (depends on 9)

A method of producing an rAAV, the method comprising:
(i) delivering to a cell a first vector encoding one or more AAV rep protein and/or one or more AAV cap protein, and the rAAV vector of claim 9;
(ii) culturing the cells under conditions allowing for packaging the rAAV; and
(iii) harvesting the cultured host cell or culture medium for collection of the rAAV.

### Claim 18 (depends on 7)

A method for treating a subject having or suspected of having Alzheimer's disease, the method comprising administering to the subject the rAAV of claim 7.

### Claim 19 (depends on 18)

The method of claim 18, wherein the administration comprises direct injection to the CNS of the subject, optionally wherein the direct injection is intracerebral injection, intraparenchymal injection, intrathecal injection, intra-cisterna magna (ICM) injection or any combination thereof.

### Claim 20 (depends on 18)

The method of claim 18, wherein the administration comprises peripheral injection, optionally wherein the peripheral injection is intravenous injection.