Methods and compositions for treating a premature stop codon-mediated disorder

Patent metadata

Field	Value
Publication number	US-10905778-B2
Application number	US-201916665526-A
Country	US
Kind code	B2
Filing date	Oct 28, 2019
Priority date	Sep 26, 2018
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

Modified tRNAs can be used to express in a mammalian cell a functional gene product encoded by a gene containing a premature stop codon and/or to treat a disease mediated by a premature stop codon.

First claim

Having described the invention, the following is claimed:

1. A method of treating Dravet syndrome in a subject in need thereof, the method comprising:
administering to the subject an effective amount of a tRNA and/or an expression vector capable of expression of the tRNA, wherein the tRNA (i) comprises an anticodon that hybridizes to the premature stop codon, and (ii) is capable of being aminoacylated with an amino acid, thereby to treat the Dravet syndrome in the subject, wherein the subject has an SCN1A gene with premature stop codon mutation selected from c.664C>T, c.1129C>T, c.1492A>T, c.1624C>T, c.1738C>T, c.1837C>T, c.2134C>T, c.2593C>T, c.3637C>T, c.3733C>T, c.3985C>T, c.4573C>T, c.5656C>T, and c.5734C>T; and wherein the tRNA comprises a nucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18.

2. The method of claim 1 , wherein the SCN1A gene is caused by a mutation selected from c.1738C>T and c.3985C>T.

3. The method of claim 1 , wherein the amino acid is selected from serine, leucine, glutamine, and arginine.

4. The method of claim 1 , wherein the tRNA comprises the nucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.

5. The method of claim 1 , wherein the expression vector comprises a nucleotide sequence selected from SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21.

6. The method of claim 1 , wherein the expression vector comprises a nucleotide sequence selected from SEQ ID NO: 5, SEQ ID NO: 8, and SEQ ID NO: 10.

Assignees

• Univ Case Western Reserve

Inventors

• Coller Jeffery M
• Sweet Thomas

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A61K48/0066 Primary

  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 · CPC title

• A61K48/005 Primary

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title