A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD
Year: 2025
Type: article
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 adeno-associated virus, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference (RNAi)-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.
Source: Molecular Therapy
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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4414568908