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

## TL;DR

A new RNA therapy targeting Hif1a and Hif2a in the eye shows promise in preventing retinal degeneration linked to age-related macular degeneration.

## Contribution

A dual-acting RNAi therapy using a single virus to target Hif1a and Hif2a in different retinal cells is introduced.

## Key findings

- The therapy preserved photoreceptors and RPE in two AMD models for up to 61 weeks.
- Dual-acting virus outperformed single-target viruses in efficacy.
- The approach targets a conserved pathway for chronic hypoxia-related diseases.

## 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.

A novel multiplexed RNA-based therapy was presented by Samardzija and colleagues, utilizing a single adeno-associated viral vector to silence two hypoxia-inducible transcription factors, Hif1a and Hif2a, in photoreceptors and the retinal pigment epithelium. This provides a potential strategy for preventing retinal degeneration by targeting common disease pathways related to hypoxia.