PXD062957

PXD062957 is an original dataset announced via ProteomeXchange.

Title	AAV-delivered engineered suppressor tRNA rescues visual function in rd12 mice
Description	WenNonsense mutations change a sense codon into a premature termination codon (PTC) in mRNA and account for approximately 18.5% of human inherited retinal diseases (IRDs)-related mutation. Nonsense suppression therapies by small molecular drugs or suppressor tRNAs (sup-tRNAs) can introduce an amino acid at PTC, thereby, promoting the production of full-length proteins. While sup-tRNA-based therapies have shown promising results in cell culture models, challenges remain for in vivo delivery, particularly regarding efficacy, stability, and safety. In this study, we engineered the body sequence of sup-tRNAArg to enhance readthrough efficiency at clinically relevant PTCs in the RPE65 and ABCA4 genes, as well as at PTCs with +4 nucleotide shifts across all four types. By using the self-complementary adeno-associated virus (scAAV), we achieved restoration of RPE65 protein expression in up to 50.2% RPE cells in a mouse model carrying the RPE65-R44X nonsense mutation. Notably, the engineered sup-tRNAArg significantly restored retinal function and visual-guided behavior in mice, with effects lasting for at least 12 weeks. Furthermore, scAAV8.sup-tRNAArg exhibited minimal retinal toxicity and had negligible effects on the activation of unfolded protein response pathways, which is related to readthrough at normal stop codons. Our findings demonstrate the potential of scAAV-delivered sup-tRNAArg as a translatable therapeutic intervention for inherited retinal diseases harboring nonsense mutations.
HostingRepository	iProX
AnnounceDate	2025-04-14
AnnouncementXML	Submission_2025-04-14_20:10:42.764.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chengda Ren
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-14 20:10:28	ID requested
⏵ 1	2025-04-14 20:10:43	announced

Dataset with its publication pending

submitter keyword: Suppressor tRNA, Gene therapy, Inherited retinal diseases, Adeno-associated virus

Yang Yang
contact affiliation	Department of Ophthalmology, West China Hospital, Sichuan University
contact email	yang2012@scu.edu.cn
lab head
Chengda Ren
contact affiliation	Department of Ophthalmology, West China Hospital, Sichuan University
contact email	drren@wchscu.cn
dataset submitter

iProX dataset URI