Methods of Rescuing Stop Codons via Genetic Reassignment with ACE-tRNA

Patent metadata

Field	Value
Publication number	US-2025115905-A1
Application number	US-202418430760-A
Country	US
Kind code	A1
Filing date	Feb 2, 2024
Priority date	Nov 2, 2017
Publication date	Apr 10, 2025
Grant date	—

Abstract

The present invention provides compositions and methods for treating diseases and disorders associated with premature termination codons comprising administration of nucleic acid molecules comprising or encoding anticodon edited tRNAs.

First claim

1 . A method of treating a disease associated with a premature termination codon (PTC) in a subject in need thereof, the method comprising administering to the subject a composition for generating one or more anticodon edited tRNA (ACE-tRNA) or fragments thereof in a subject, comprising one or more nucleic acid molecules or fragments thereof, wherein the composition is formulated for administration by electroporation.

2 . The method of claim 1 , wherein the composition comprises a cDNA molecule encoding an ACE-tRNA.

3 . The method of claim 1 , wherein the composition comprises a RNA molecule comprising an ACE-tRNA.

4 . The method of claim 1 wherein the one or more nucleic acid molecules are engineered to be in an expression vector.

5 . The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable excipient.

6 . (canceled)

7 . The method of claim 1 , wherein the disease is a disease or disorder associated with a UGA PTC, and further wherein the method comprises administering at least one ACE-tRNA specific for UGA.

8 . The method of claim 1 , wherein the disease is a disease or disorder associated with a UAA PTC, and further wherein the method comprises administering at least one ACE-tRNA specific for UAA.

9 . The method of claim 1 , wherein the disease is a disease or disorder associated with a UAG PTC, and further wherein the method comprises administering at least one ACE-tRNA specific for UAG.

10 . The method of claim 1 , wherein the method comprises administering at least two ACE-tRNA, wherein each of the at least two ACE-RNA are specific for at least two different amino acid molecules onto a polypeptide chain.

11 . The method of claim 1 , wherein the method comprises administering at least two ACE-tRNA, wherein each of the at least two ACE-tRNA are specific for incorporating the same amino acid molecule onto a polypeptide chain.

12 . The method of claim 1 , wherein the the one or more ACE-tRNA are encoded on the same nucleic acid molecule.

13 . The method of claim 1 , wherein the the one or more ACE-tRNA are encoded on different nucleic acid molecules.

14 . The method of claim 7 , wherein the at least one ACE-tRNA specific for UGA selected from the group consisting of ACE-tRNAArg, ACE-tRNAGly and ACE-tRNATrp.

15 . The method of claim 1 , wherein the disease is selected from the group consisting of Duchenne or Becker muscular dystrophy, retinoblastoma, neurofibromatosis, ataxia telangiectasia, Tay-Sachs disease, cystic fibrosis, Wilm's tumor, hemophilia A, hemophilia B, Menkes disease, Ullrich's disease, β-Thalassemia, type 2A or type 3 von Willebrand disease, Robinow syndrome, brachydactyly type B (shortening of digits and metacarpals), inherited susceptibility to mycobacterial infection, inherited retinal disease, inherited bleeding tendency, inherited blindness, congenital neurosensory deafness, colonic agangliosis, inherited neural develop mental defect including neurosensory deafness, peripheral neuropathy, central demyelinating leukodystrophy, Liddle's syndrome, xeroderma pigmentosum, Fanconi's anemia, anemia, hypothyroidism, p53-associated cancers (e.g., p53-associated squamous cell carcinoma, p53-associated hepatocellular carcinoma, p53-associated ovarian carcinoma), esophageal carcinoma, osteocarcinoma, ovarian carcinoma, hepatocellular carcinoma, breast cancer, fibrous histiocytoma, SRY sex reversal, triosephosphate isomerase-anemia, diabetes, and rickets.

16 . The method of claim 1 , wherein the subject is a mammal.

Assignees

• Wistar Inst
• Univ Iowa Res Found

Inventors

• Puchalt Alfredo Perales
• Lueck John
• Ahern Christopher A
• Weiner David B

Classifications

• A61P43/00 Primary

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C12N15/11 Primary

  DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• A61K31/7105

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title