Methods and compositions related to trna therapeutics for treating vision loss

Patent metadata

Field	Value
Publication number	US-2025257354-A1
Application number	US-202318857516-A
Country	US
Kind code	A1
Filing date	Apr 21, 2023
Priority date	Apr 21, 2022
Publication date	Aug 14, 2025
Grant date	—

Abstract

Provided herein are compositions and methods related to tRNA therapeutics for treating vision loss and blindness.

First claim

What is claimed is:

1 . A method of reading through one or more premature termination codons (PTCs) in cells of the eye, comprising delivering one or more of the tRNAs, one or more of the oligonucleotide(s) encoding the tRNA(s), one or more of the vector(s) encoding the tRNA(s), one or more of the expression cassette(s) encoding the tRNA(s), or one or more of the composition(s) comprising any of the foregoing provided herein to cells of the eye in an amount effective to read through the one or more PTCs.

2 . A method of restoring protein function in cells of the eye, comprising delivering one or more of the tRNAs, one or more of the oligonucleotide(s) encoding the tRNA(s), one or more of the vector(s) encoding the tRNA(s), one or more of the expression cassette(s) encoding the tRNA(s), or one or more of the composition(s) comprising any of the foregoing provided herein to cells of the eye in an amount effective to restore protein function in the cells.

3 . A method of restoring vision in a subject, comprising administering one or more of the tRNAs, one or more of the oligonucleotide(s) encoding the tRNA(s), one or more of the vector(s) encoding the tRNA(s), one or more of the expression cassette(s) encoding the tRNA(s), or one or more of the composition(s) comprising any of the foregoing provided herein to cells of the eye in an amount effective to restore vision in the subject.

4 . The method of claim 3 , wherein the administration is by subretinal injection.

5 . The method of claim 3 , wherein the administration is by intravitreal injection.

6 . The method of any one of claims 3-5 , wherein the subject is a human.

7 . The method of any one of the preceding claims , wherein the cells are photoreceptor cells.

8 . The method of any one of claims 1-6 , wherein the cells are retinal pigment epithelial cells.

9 . The method of any one of the preceding claims wherein the cells are iPSCs.

10 . The method of any one of the preceding claims , wherein the one or more oligonucleotide(s) or one or more expression cassette(s) are DNA, such as cDNA.

11 . The method of any one of the preceding claims , wherein the one or more oligonucleotide(s) or one or more expression cassette(s) are in the form of a plasmid.

12 . The method of any one of the preceding claims , wherein the one or more of the oligonucleotide(s) or one or more of the expression cassette(s) are in the form of a minicircle.

13 . The method of any one of claims 1-9 , wherein the vector is a viral vector.

14 . The method of claim 13 , wherein the viral vector is an AAV vector.

15 . The method of claim 14 , wherein the AAV vector is an AAV2, AAV5, AAV9, AAV2/9, AAV7m8 or AAV2.7m8 vector.

16 . The method of any one of the preceding claims , wherein at least two or at least three of any of the tRNAs provided herein are delivered or administered.

17 . The method of any one of claims 1-15 , wherein the at least two or at least three of tRNAs provided herein are encoded by the one or more oligonucleotide(s), one or more vector(s), one or more expression cassette(s), or are comprised in one or more of the composition(s).

18 . The method of any one of the preceding claims , wherein the one or more of the tRNAs are ArgtRNA(s), TrptRNA(s) and/or GlutRNA(s).

19 . The method of any one of the preceding claims , wherein the one or more of the tRNAs, one or more of the oligonucleotide(s) encoding the tRNA(s), one or more of the vector(s) encoding the tRNA(s), one or more of the expression cassette(s) encoding the tRNA(s), or one or more of the composition(s) comprising any of the foregoing provided herein are comprised in a delivery vehicle.

20 . The method of claim 19 , wherein the delivery vehicle is a particle.

21 . The method of claim 20 , wherein the particle is a lipid-based particle, such as a liposome.

22 . The method of claim 20 , wherein the particle is a polymer-based particle.

23 . The method of claim 20 , wherein the particle is a silica nanoparticle (SNP).

24 . The method of claim 23 , wherein the SNP is delivered or administered as a population of SNPs.

25 . The method of claim 24 , wherein the SNPs are conjugated to HA.

26 . The method of claim 25 , wherein the molecular weight of the HA is in the range of 10 kDa-1MDa, such as any one specific molecular weights provided herein.

27 . The method of any one of claims 23-26 , wherein the SNP(s) has surface amine groups, such as APTES amine groups.

28 . The method of claim 27 , wherein the molar ratio of APTES to total silica of the SNP(s) is in the range of 10-30%, such as any one specific molar ratio provided herein.

29 . The method of claim 27 or 28 , wherein the molar ration of HA saccharide unit to APTES of the SNP(s) is 5-15, such as any one specific molar ratio provided herein.

30 . The method of any one of claims 23-29 , wherein the SNP(s) are conjugated to a targeting ligand or cell penetrating peptide (CPP), such as any one of the targeting ligands or CPPs provided herein.

31 . The method of claim 30 , wherein the molar ratio of targeting ligand or CPP to HA is 10-30%, such as any one specific molar ratio provided herein.

32 . The method of any one of claims 25-31 , wherein the substitution degree of HA to targeting ligand or CPP conjugate is 1-40%, such as any one specific substitution degree provided herein.

33 . The method of any one of claims 23-32 , wherein the SNP(s) are conjugated to PEG.

34 . The method of claim 33 , wherein the PEG links the targeting ligand or CPP to the SNP(s).

35 . The method of claim 33 or 34 , wherein the weight ratio of PEG/SNP is 1/10-3/10, such as any specific weight ratio provided herein.

36 . The method of any one of claims 33-35 , wherein the targeting ligand or CPP ratio to PEG is 1-60, such as any one specific ratio provided herein.

37 . The method of any one of claim 30 or 31 , wherein the targeting ligand or CPP is conjugated to the SNP(s) with a spacer, such as OEG.

38 . The method of claim 37 , wherein the OEG has a molecular weight of 200 Da-1 kDa, such as any one specific molecular weight provided herein.

39 . The method of any one of claims 23-38 , wherein the average dimension of the SNP(s) is between 40-60 nm, such as any one specific average dimension provided herein.

40 . A composition comprising the tRNA(s), oligonucleotide(s), vector(s), expression cassette(s) or composition(s) of any one of the preceding claims .

41 . A composition comprising the delivery vehicle or population of delivery vehicles, such as the particles, of any one of claims 19-40 .

42 . The composition of claim 40 or 41 , further comprising a pharmaceutically acceptable carrier.

43 . A cell comprising the tRNA(s), oligonucleotide(s), vector(s), expression cassette(s) or composition(s) of any one of the preceding claims .

44 . The cell of claim 43 , wherein the cell is a photoreceptor cell.

45 . The cell of claim 43 , wherein the cell is a retinal pigment epithelial cell.

46 . The cell of any on

Assignees

• Univ Iowa Res Found
• Wisconsin Alumni Res Found

Inventors

• Ahern Christopher
• Pattnaik Bikash
• Gong Shaoqin
• Wang Yuyuan

Classifications

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• C12N2320/34

  Allele or polymorphism specific uses · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N15/86 Primary

  Viral vectors · CPC title

• A61K48/005

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