# US 11,999,974 B2 · Gene therapies for lysosomal disorders

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- Number: US 11,999,974 B2
- Document ID: US11999974B2
- Status: Granted
- Kind: B2
- Application number: 16/846,065
- Filed: 2020-04-10
- Published: 2020-10-22
- Granted: 2024-06-04
- Earliest claimed: 2019-04-10
- Assignees: Prevail Therapeutics, Inc.
- Applicants: Prevail Therapeutics, Inc.
- Inventors: Asa Abeliovich; Laura Heckman; Herve Rhinn; Li Chin Wong; Hsuan-Ni Lin; Franz Hefti
- Web page: https://patentgrep.com/patent/US11999974B2

## CPC

- C07K 14/475: Growth factors; Growth regulators
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61K 48/0083: {characterised by an aspect of the administration regime}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07K 14/435: from animals; from humans
- C12N 9/0071: {acting on paired donors with incorporation of molecular oxygen (1.14)}
- C12N 15/86: Viral vectors
- C12Y 114/18001: Tyrosinase (1.14.18.1)
- G01N 33/6803: {General methods of protein analysis not limited to specific proteins or families of proteins}
- C12N 2750/14132: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2750/14133: Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- G01N 2333/435: from animals; from humans
- 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)
- 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
- C12Y: ENZYMES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## 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.

## Claims

### Claim 1

A method for treating a subject having fronto-temporal dementia with a GRN mutation, the method comprising administering to the subject a recombinant adeno-associated virus (rAAV) comprising:
(i) a rAAV vector comprising a nucleic acid comprising 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
(ii) an AAV9 capsid protein;
wherein the rAAV is administered via an injection into the cisterna magna.

### Claim 2 (depends on 1)

The method of claim 1, wherein the rAAV is administered to the subject at a dose ranging from about 1×1013 vector genomes (vg) to about 7×1014 vg.

### Claim 3 (depends on 1)

The method of claim 1, wherein the promoter is a chicken beta actin (CBA) promoter.

### Claim 4 (depends on 1)

The method of claim 1, wherein the rAAV vector further comprises a cytomegalovirus (CMV) enhancer.

### Claim 5 (depends on 1)

The method of claim 1, wherein the rAAV vector further comprises a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE).

### Claim 6 (depends on 1)

The method of claim 1, wherein the rAAV vector further comprises a Bovine Growth Hormone polyA signal tail.

### Claim 7 (depends on 1)

The method of claim 1, wherein the nucleic acid comprises two adeno-associated virus inverted terminal repeats (ITR) sequences flanking the expression construct, wherein the first ITR sequence is a 5′ ITR, and the second ITR sequence is a 3′ ITR.

### Claim 8 (depends on 7)

The method of claim 7, wherein each of the two ITR sequences is a wild-type AAV2 ITR sequence.

### Claim 9 (depends on 7)

The method of claim 7, wherein the rAAV vector further comprises a TRY region between the 5′ ITR and the expression construct, wherein the TRY region comprises SEQ ID NO: 28.

### Claim 10 (depends on 1)

The method of claim 1, wherein the rAAV is administered in a formulation comprising about 20 mM Tris, pH 8.0, about 1 mM MgCl2, about 200 mM NaCl, and about 0.001% w/v poloxamer 188.

### Claim 11

A method for treating a subject having fronto-temporal dementia with a GRN mutation, the method comprising administering to the subject a rAAV comprising:
(i) a rAAV vector comprising a nucleic acid comprising, in 5′ to 3′ order:
(a) an AAV2 ITR;
(b) a CMV enhancer;
(c) a CBA promoter;
(d) a transgene insert encoding a PGRN protein, wherein the transgene insert comprises the nucleotide sequence of SEQ ID NO: 68;
(e) a WPRE;
(f) a Bovine Growth Hormone polyA signal tail; and
(g) an AAV2 ITR; and
(ii) an AAV9 capsid protein;
wherein the rAAV is administered via an injection into the cisterna magna.

### Claim 12 (depends on 11)

The method of claim 11, wherein the rAAV is administered to the subject at a dose ranging from about 1×1013 vg to about 7×1014 vg.

### Claim 13 (depends on 11)

The method of claim 11, wherein the rAAV is administered in a formulation comprising about 20 mM Tris, pH 8.0, about 1 mM MgCl2, about 200 mM NaCl, and about 0.001% w/v poloxamer 188.