A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD.

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

Laboratory for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Wagistrasse 14, Schlieren, 8952, Zurich, Switzerland. · pubmed

Paper

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.

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Research summary

The paper claims that a novel multiplex RNAi therapy targeting Hif1a and Hif2a can preserve photoreceptors and retinal pigment epithelium in models of age-related macular degeneration. This research is relevant as it addresses a mechanism related to hypoxia and its impact on aging tissues, specifically in the context of age-related macular degeneration, which is a significant age-related disease.

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