Authors
Andrea E Dillinger, Herbert Jaegle, Holger Fuchs, Benjamin Strobel, Norbert Redemann, Ernst R Tamm
Published in
Molecular therapy. Advances. Volume 34. Issue 3. Pages 201795. Sep 10, 2026. Epub Jun 24, 2026.
Abstract
Norrin, secreted by retinal Müller cells, activates canonical Wnt signaling via Frizzled-4 and co-receptors. Loss-of-function mutations abolish intraretinal capillary formation in mice. In humans, mutations in NDP, which encodes norrin, cause Norrie disease, characterized by retinal hypovascularization and congenital blindness, and X-linked familial exudative vitreoretinopathy (FEVR), resembling retinopathy of prematurity (ROP). We evaluated adeno-associated viral (AAV) vectors expressing norrin as gene therapy for Norrie disease, FEVR, and ROP. AAV2-7m8 and AAV-ShH10 were tested in juvenile wild-type and norrin-deficient (Ndp KO) mice via intravitreal injection at postnatal day 7, with some mice subjected to oxygen-induced retinopathy (OIR). AAV2-7m8 transduced Müller glia, while AAV-ShH10 targeted retinal ganglion cells. Both vectors fully restored intraretinal capillary growth in Ndp KO mice, normalizing vessel density and plexus organization, preserving the blood-retinal barrier, and rescuing visual function. In OIR, scAAV2-7m8-huNorrin reduced vaso-obliteration and neovascular tuft formation, increasing deep plexus coverage, and suppressed Vegfa164 and Ang-2 upregulation. The findings demonstrate that AAV-mediated norrin delivery efficiently targets retinal glia and neurons, restores vascular structure and function, stabilizes the blood-retinal barrier, and mitigates OIR-induced pathological angiogenesis, supporting its potential as a therapeutic strategy for Norrie-related retinopathies and ROP.
PMID:
42436854
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.
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