Products and methods for inhibition of expression of mutant gars protein
AssigneesResearch Institute At Nationwide Children's Hospital, The Jackson Laboratory
InventorsScott Quenton Harper, Robert W. Burgess
Life of this patent
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Abstract
RNA interference-based methods and products for inhibiting the expression of mutant Glycyl-tRNA Synthetase (GARS) genes are provided. Delivery vehicles such as recombinant adeno-associated viruses deliver DMAs encoding GARS microRNAs, as well as a replacement GARS gene that is resistant to knock down by the microRNAs. The methods have application in the treatment of N diseases or disorders associated with mutant GARS including, but not limited to, Charcot-Marie-Tooth Disease Type 2D (CMT2D).
Claims38
A nucleic acid comprising
- (a) a nucleic acid encoding a Glycyl-tRNA Synthetase (GARS) miRNA comprising at least about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the polynucleotide sequence set forth in any one of SEQ ID NOs:
- 1-25;
- (b) a nucleic acid encoding a GARS guide strand comprising at least about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the polynucleotide sequence set forth in any one of SEQ ID NOs:
- 26-50;
- or
- (c) a nucleic acid encoding a GARS miRNA comprising at least about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the polynucleotide sequence set forth in any one of SEQ ID NOs:
- 1-25 and a nucleic acid comprising an RNAi-resistant GARS gene comprising at least about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the polynucleotide sequence set forth in any one of SEQ ID NOs:
- 51-57.
A composition comprising a delivery vehicle capable of delivering agents to a neuronal cell and
- (a) a nucleic acid comprising an RNAi-resistant human GARS gene;
- (b) a nucleic acid encoding a miRNA, wherein the miRNA binds a segment of a messenger RNA (mRNA) encoded by a human Glycyl-tRNA Synthetase (GARS) gene, the segment is conserved relative to the wild-type mouse GARS gene, and the segment does not encode sequence comprising a mutation associated with CMT2D;
- or
- (c) a combination of (a) and (b) and;
- optionally,
- (d) a pharmaceutically acceptable carrier.
The composition of claim 16, wherein the nucleic acid comprising the RNAi-resistant human GARS gene comprises a polynucleotide comprising at least about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence of any one of SEQ ID NOs:
- 51-57.
The composition of any one of claims 16-21, wherein the delivery vehicle is a viral vector.
Dependencies are inferred from the claim text.