Dual-acting gene therapy targeting HIF1A and HIF2A by RNA interference mitigates retinal degeneration in two mouse models of AMD

Ebner, L. J. A.; Imsand, C.; Karademir, D.; Peters, F.; Kiessling, E.; Fottner, A.; Matter, C.; Fajardo, D. S.; Merolla, L.; Woegenstein, G. M.; Tsioti, I.; Govers, L. P.; Blaser, F.; Meneau, I.; Boye, S. L.; Boye, S. E.; Grimm, C.; Samardzija, M.

doi:10.1101/2024.11.29.626080

bioRxiv · 10.1101/2024.11.29.626080

Dual-acting gene therapy targeting HIF1A and HIF2A by RNA interference mitigates retinal degeneration in two mouse models of AMD

Ebner, L. J. A.·Imsand, C.·Karademir, D.·Peters, F.·Kiessling, E.·Fottner, A.·Matter, C.·Fajardo, D. S.·Merolla, L.·Woegenstein, G. M.·Tsioti, I.·Govers, L. P.·Blaser, F.·Meneau, I.·Boye, S. L.·Boye, S. E.·Grimm, C.·Samardzija, M.

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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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Ebner, L. J. A., Imsand, C., Karademir, D., Peters, F., Kiessling, E., Fottner, A., Matter, C., Fajardo, D. S., Merolla, L., Woegenstein, G. M., Tsioti, I., Govers, L. P., Blaser, F., Meneau, I., Boye, S. L., Boye, S. E., Grimm, C., Samardzija, M.. 2024-11-30. Dual-acting gene therapy targeting HIF1A and HIF2A by RNA interference mitigates retinal degeneration in two mouse models of AMD. https://doi.org/10.1101/2024.11.29.626080

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