Lynn J A Ebner, Cornelia Imsand, Duygu Karademir, Florian Peters, Eva Kiessling, Antonia Fottner, Claudia Matter, Diego S Fajardo, Luca Merolla, Gabriele M Wögenstein, Ioanna Tsioti, Larissa P Govers, Frank Blaser, Isabelle Meneau, Sanford L Boye, Shannon E Boye, Christian Grimm, Marijana Samardzija
{"title":"A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD.","authors":"Lynn J A Ebner, Cornelia Imsand, Duygu Karademir, Florian Peters, Eva Kiessling, Antonia Fottner, Claudia Matter, Diego S Fajardo, Luca Merolla, Gabriele M Wögenstein, Ioanna Tsioti, Larissa P Govers, Frank Blaser, Isabelle Meneau, Sanford L Boye, Shannon E Boye, Christian Grimm, Marijana Samardzija","doi":"10.1016/j.ymthe.2025.09.044","DOIUrl":null,"url":null,"abstract":"<p><p>Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE), and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single AAV, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting only Hif1a in photoreceptors or Hif2a in the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0000,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.09.044","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE), and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single AAV, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting only Hif1a in photoreceptors or Hif2a in the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.
期刊介绍：
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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