# US 11,027,000 B2 · AADC polynucleotides for the treatment of Parkinson's disease

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- Number: US 11,027,000 B2
- Document ID: US11027000B2
- Status: Granted
- Kind: B2
- Application number: 16/540,375
- Filed: 2019-08-14
- Published: 2019-11-28
- Granted: 2021-06-08
- Earliest claimed: 2014-11-05
- Assignees: Voyager Therapeutics, Inc.
- Applicants: Voyager Therapeutics, Inc.
- Inventors: Robert Kotin; Adrian Philip Kells; Bernard Ravina
- Web page: https://patentgrep.com/patent/US11027000B2

## CPC

- A61K 38/51: Lyases (4)
- A61K 35/76: Viruses; Subviral particles; Bacteriophages
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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 9/88: Lyases (4.)
- C12N 15/86: Viral vectors
- C12Y 401/01028: Aromatic-L-amino-acid decarboxylase (4.1.1.28), i.e. tryptophane-decarboxylase
- C12N 2750/14121: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2800/22: Vectors comprising a coding region that has been codon optimised for expression in a respective host
- C12N 2830/42: being an intron or intervening sequence for splicing and/or stability of RNA
- C12N 2830/50: regulating RNA stability, not being an intron, e.g. poly A signal
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The disclosure relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides encoding AADC for the treatment of Parkinson's Disease.

## Claims

### Claim 1

A polynucleotide comprising:
a) a 5′ inverted terminal repeat (ITR), wherein said 5′ ITR is 141 nucleotides in length,
b) a cytomegalovirus (CMV) sequence region comprising from 5′ to 3′ a CMV enhancer or a fragment thereof comprising at least 250 nucleotides, and a CMV promoter or a fragment thereof comprising at least 150 nucleotides,
c) an immediate early 1 (IE1) sequence region comprising an IE1 exon1 or a fragment thereof of at least 50 nucleotides, and an IE1 intron 1 or a fragment thereof of at least 20 nucleotides,
d) a human beta globin (HB) sequence region comprising an HB intron 2 or a fragment thereof of at least 250 nucleotides, and an HB exon 3 or a fragment thereof of at least 40 nucleotides,
e) a polynucleotide sequence encoding Aromatic L-Amino Acid Decarboxylase (AADC) or an isoform thereof,
f) a poly(A) signal sequence region comprising a human growth hormone (hGH) poly(A) signal or a fragment thereof of at least 200 nucleotides, and
g) a 3′ ITR, wherein said 3′ ITR is 141 nucleotides in length;
wherein the polynucleotide comprises a nucleotide sequence at least 95% identical to SEQ ID NO: 17.

### Claim 2 (depends on 1)

The polynucleotide of claim 1, wherein the 5′ ITR and the 3′ ITR are derived from AAV2.

### Claim 3 (depends on 1)

The polynucleotide of claim 1, wherein the CMV sequence region is 507 nucleotides in length.

### Claim 4 (depends on 1)

The polynucleotide of claim 1, wherein the IE1 sequence region is 166 nucleotides in length.

### Claim 5 (depends on 1)

The polynucleotide of claim 1, wherein the HB sequence region is 400 nucleotides in length.

### Claim 6 (depends on 1)

The polynucleotide of claim 1, wherein the polynucleotide sequence encoding AADC or an isoform thereof is 1440, 1443, or 1449 nucleotides in length.

### Claim 7 (depends on 1)

The polynucleotide of claim 1, wherein the polynucleotide sequence encoding AADC or an isoform thereof is 1440 nucleotides in length.

### Claim 8 (depends on 1)

The polynucleotide of claim 1, wherein the poly(A) signal sequence region is 477 nucleotides in length.

### Claim 9 (depends on 1)

The polynucleotide of claim 1, wherein the CMV sequence region is 507 nucleotides in length, the IE1 sequence region is 166 nucleotides in length, the HB sequence region is 400 nucleotides in length, the polynucleotide sequence encoding AADC or a variant or isoform thereof is 1440 nucleotides in length, and the poly(A) signal region is 477 nucleotides in length.

### Claim 10 (depends on 1)

The polynucleotide of claim 1, wherein the 5′ ITR consists of nucleotides 1-141 of SEQ ID NO: 17.

### Claim 11 (depends on 1)

The polynucleotide of claim 1, wherein the 3′ ITR consists of nucleotides 3357-3497 of SEQ ID NO: 17.

### Claim 12 (depends on 9)

The polynucleotide of claim 9, wherein the 5′ ITR consists of nucleotides 1-141 of SEQ ID NO: 17, the 3′ ITR consists of nucleotides 3357-3497 of SEQ ID NO: 17, or the 5′ ITR consists of nucleotides 1-141 of SEQ ID NO: 17 and the 3′ ITR consists of nucleotides 3357-3497 of SEQ ID NO: 17.

### Claim 13 (depends on 1)

A recombinant adeno-associated virus (rAAV) comprising an adeno-associated virus (AAV) vector genome and an AAV capsid, wherein the AAV vector genome comprises the polynucleotide of claim 1.

### Claim 14 (depends on 12)

A recombinant adeno-associated virus (rAAV) comprising an adeno-associated virus (AAV) vector genome and an AAV capsid, wherein the AAV vector genome comprises the polynucleotide of claim 12.

### Claim 15 (depends on 13)

The rAAV of claim 13, wherein the AAV capsid is AAV2, AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.47, AAV9(hu14), AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAV-DJ or AAV-DJ8.

### Claim 16 (depends on 14)

The rAAV of claim 14, wherein the AAV capsid is AAV2, AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.47, AAV9(hu14), AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAV-DJ or AAV-DJ8.

### Claim 17 (depends on 15)

The rAAV of claim 15, wherein the AAV capsid is AAV2.

### Claim 18 (depends on 16)

The rAAV of claim 16, wherein the AAV capsid is AAV2.

### Claim 19 (depends on 17)

A pharmaceutical composition comprising the rAAV of claim 17 and a pharmaceutically acceptable excipient.

### Claim 20 (depends on 18)

A pharmaceutical composition comprising the rAAV of claim 18 and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 19)

The pharmaceutical composition of claim 19, wherein at least 70% of the rAAV vectors contain an AAV vector genome.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein at least 70% of the rAAV vectors contain an AAV vector genome.

### Claim 23 (depends on 19)

A method of increasing the level of Aromatic L-Amino Acid Decarboxylase (AADC) protein in a subject comprising administering an effective amount of the pharmaceutical composition of claim 19.

### Claim 24 (depends on 23)

The method of claim 23, wherein the subject has Parkinson's Disease.

### Claim 25 (depends on 20)

A method of increasing the level of Aromatic L-Amino Acid Decarboxylase (AADC) protein in a subject comprising administering an effective amount of the pharmaceutical composition of claim 20.

### Claim 26 (depends on 25)

The method of claim 25, wherein the subject has Parkinson's Disease.