# US 10,307,469 B2 · Synthetic methylmalonyl-CoA mutase transgene for the treatment of MUT class methylmalonic acidemia (MMA)

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- Number: US 10,307,469 B2
- Document ID: US10307469B2
- Status: Granted
- Kind: B2
- Application number: 15/633,964
- Filed: 2017-06-27
- Published: 2017-11-16
- Granted: 2019-06-04
- Earliest claimed: 2013-03-15
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The United States of America, as represented by the Secretary, Dept. of Health and Human Services
- Inventors: Charles P. Venditti; Randy J. Chandler
- Web page: https://patentgrep.com/patent/US10307469B2

## CPC

- A61K 38/52: Isomerases (5)
- A61K 48/0066: {Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid}
- C12N 9/90: Isomerases (5.)
- C12Y 504/99002: Methylmalonyl-CoA mutase (5.4.99.2)
- 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)
- 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

Synthetic polynucleotides encoding human methylmalonyl-CoA mutase (synMUT) and exhibiting augmented expression in cell culture and/or in a subject are described herein. An adeno-associated viral (AAV) gene therapy vector encoding synMUT under the control of a liver-specific promoter (AAV2/8-HCR-hAAT-synMUT-RBG) successfully rescued the neonatal lethal phenotype displayed by methylmalonyl-CoA mutase-deficient mice, lowered circulating methylmalonic acid levels in the treated animals, and resulted in prolonged hepatic expression of the product of synMUT transgene in vivo, human methylmalonyl-CoA mutase (MUT).

## Claims

### Claim 1

A method of treating a disease or condition mediated by methylmalonyl-CoA mutase, comprising administering to a subject in need thereof a therapeutic amount of a methylmalonyl-CoA mutase produced using a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMUT) selected from the group consisting of:
(a) a polynucleotide comprising the nucleic acid sequence of SEQ ID NO:1; and
(b) a codon-optimized polynucleotide comprising a polynucleotide having a nucleic acid sequence with at least about 80% identity to the nucleic acid sequence of SEQ ID NO:1 and encoding a polypeptide according to SEQ ID NO:2, and having equivalent expression in a host to either SEQ ID NO:1 expression or SEQ ID NO:3 expression,
wherein the codon-optimized polynucleotide having at least about 80% identity to SEQ ID NO:1 does not have the nucleic acid sequence of SEQ ID NO:3.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease or condition is methylmalonic academia (MMA).

### Claim 3 (depends on 1)

The method of claim 1, wherein the polynucleotide has at least about 90% identity to the nucleic acid sequence of SEQ ID NO:1.

### Claim 4 (depends on 1)

The method of claim 1, wherein the polynucleotide has at least about 95% identity to the nucleic acid sequence of SEQ ID NO:1.

### Claim 5 (depends on 1)

The method of claim 1, wherein the polynucleotide has at least about 97% identity to the nucleic acid sequence of SEQ ID NO:1.

### Claim 6 (depends on 1)

The method of claim 1, wherein the polynucleotide has at least about 99% identity to the nucleic acid sequence of SEQ ID NO:1.

### Claim 7 (depends on 1)

The method of claim 1, wherein the synthetic methylmalonyl-CoA mutase (MUT) polynucleotide exhibits increased expression in an appropriate host relative to the expression SEQ ID NO:3 in an appropriate host.

### Claim 8 (depends on 7)

The method of claim 7, wherein the synthetic polynucleotide having increased expression comprises a nucleic acid sequence comprising codons that have been optimized relative to the naturally occurring human methylmalonyl-CoA mutase polynucleotide sequence (SEQ ID NO:3).

### Claim 9 (depends on 7)

The method of claim 7, wherein the nucleic acid sequence has at least about 70% of less commonly used codons replaced with more commonly used codons.

### Claim 10 (depends on 1)

The method of claim 1, wherein the methylmalonyl-CoA mutase is formulated with a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

The method of claim 1, wherein the administering of the methylmalonyl-CoA mutase comprises administering an expression vector comprising the synthetic methylmalonyl-CoA mutase polynucleotide and expression of the polynucleotide in the subject.