<?xml version="1.0" encoding="UTF-8" standalone="yes"?>

<ProteomeXchangeDataset id="PXD062957" formatVersion="1.4.0" xsi:noNamespaceSchemaLocation="proteomeXchange-1.4.0.xsd" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
  <CvList>
    <Cv fullName="PSI-MS" uri="http://psidev.cvs.sourceforge.net/viewvc/*checkout*/psidev/psi/psi-ms/mzML/controlledVocabulary/psi-ms.obo" id="MS"/>
    <Cv fullName="PSI-MOD" uri="http://psidev.cvs.sourceforge.net/psidev/psi/mod/data/PSI-MOD.obo" id="MOD"/>
    <Cv fullName="UNIMOD" uri="http://www.unimod.org/obo/unimod.obo" id="UNIMOD"/>
  </CvList>
  <DatasetSummary announceDate="2025-04-14" hostingRepository="iProX" 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.</Description>
    <ReviewLevel>
      <cvParam cvRef="MS" accession="MS:1002854" name="Peer-reviewed dataset"/>
    </ReviewLevel>
    <RepositorySupport>
      <cvParam cvRef="MS" accession="MS:1002857" name="Unsupported dataset by repository"/>
    </RepositorySupport>
  </DatasetSummary>
  <DatasetIdentifierList>
    <DatasetIdentifier>
      <cvParam cvRef="MS" accession="MS:1001919" name="ProteomeXchange accession number" value="PXD062957"/>
    </DatasetIdentifier>
    <DatasetIdentifier>
      <cvParam cvRef="MS" accession="MS:1002836" name="iProX dataset identifier" value="IPX0011710000"/>
    </DatasetIdentifier>
  </DatasetIdentifierList>
  <DatasetOriginList>
    <DatasetOrigin>
      <cvParam cvRef="MS" accession="MS:1002868" name="Original data"/>
    </DatasetOrigin>
  </DatasetOriginList>
  <SpeciesList>
    <Species>
      <cvParam cvRef="MS" accession="MS:1001469" name="taxonomy: scientific name" value="Mus musculus"/>
      <cvParam cvRef="MS" accession="MS:1001467" name="taxonomy: NCBI TaxID" value="10090"/>
    </Species>
  </SpeciesList>
  <InstrumentList>
    <Instrument id="Instrument_1">
      <cvParam cvRef="MS" accession="MS:1002732" name="Orbitrap Fusion Lumos"/>
    </Instrument>
  </InstrumentList>
  <ModificationList>
    <cvParam cvRef="MS" accession="MS:1002864" name="No PTMs are included in the dataset"/>
  </ModificationList>
  <ContactList>
    <Contact id="project_submitter">
      <cvParam cvRef="MS" accession="MS:1000586" name="contact name" value="Chengda Ren"/>
      <cvParam cvRef="MS" accession="MS:1000589" name="contact email" value="drren@wchscu.cn"/>
      <cvParam cvRef="MS" accession="MS:1000590" name="contact affiliation" value="Department of Ophthalmology, West China Hospital, Sichuan University"/>
      <cvParam cvRef="MS" accession="MS:1002037" name="dataset submitter"/>
    </Contact>
    <Contact id="project_lab_head">
      <cvParam cvRef="MS" accession="MS:1002332" name="lab head"/>
      <cvParam cvRef="MS" accession="MS:1000586" name="contact name" value="Yang Yang"/>
      <cvParam cvRef="MS" accession="MS:1000589" name="contact email" value="yang2012@scu.edu.cn"/>
      <cvParam cvRef="MS" accession="MS:1000590" name="contact affiliation" value="Department of Ophthalmology, West China Hospital, Sichuan University"/>
    </Contact>
  </ContactList>
  <PublicationList>
    <Publication id="pending">
      <cvParam cvRef="MS" accession="MS:1002858" name="Dataset with its publication pending"/>
    </Publication>
  </PublicationList>
  <KeywordList>
    <cvParam cvRef="MS" accession="MS:1001925" name="submitter keyword" value="Suppressor tRNA, Gene therapy, Inherited retinal diseases, Adeno-associated virus"/>
  </KeywordList>
  <FullDatasetLinkList>
    <FullDatasetLink>
      <cvParam cvRef="MS" accession="MS:1002837" name="iProX dataset URI" value="http://www.iprox.org/page/project.html?id=IPX0011710000"/>
    </FullDatasetLink>
  </FullDatasetLinkList>
  <DatasetFileList>
    <DatasetFile id="FILE_0" name="TCT1.mzIdentML">
      <cvParam cvRef="MS" accession="MS:1002848" name="Result file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/TCT1.mzIdentML"/>
    </DatasetFile>
    <DatasetFile id="FILE_1" name="A4T1.mzIdentML">
      <cvParam cvRef="MS" accession="MS:1002848" name="Result file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/A4T1.mzIdentML"/>
    </DatasetFile>
    <DatasetFile id="FILE_2" name="RPE65.mzIdentML">
      <cvParam cvRef="MS" accession="MS:1002848" name="Result file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/RPE65.mzIdentML"/>
    </DatasetFile>
    <DatasetFile id="FILE_3" name="search.rar">
      <cvParam cvRef="MS" accession="MS:1002850" name="Peak list file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/search.rar"/>
    </DatasetFile>
    <DatasetFile id="FILE_4" name="TCT1.raw">
      <cvParam cvRef="MS" accession="MS:1002846" name="Associated raw file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/TCT1.raw"/>
    </DatasetFile>
    <DatasetFile id="FILE_6" name="A4T1.raw">
      <cvParam cvRef="MS" accession="MS:1002846" name="Associated raw file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/A4T1.raw"/>
    </DatasetFile>
    <DatasetFile id="FILE_7" name="RPE65.raw">
      <cvParam cvRef="MS" accession="MS:1002846" name="Associated raw file URI" value="http://download.iprox.org/IPX0011710000/IPX0011710001/RPE65.raw"/>
    </DatasetFile>
  </DatasetFileList>
</ProteomeXchangeDataset>