AAV-DJ-Mediated MYOC Silencing as a Gene Therapy Approach for Myocilin-Associated Glaucoma.

PURPOSE: To evaluate the therapeutic efficacy of an adeno-associated virus serotype DJ (AAV-DJ) vector delivering MYOC-targeting short-hairpin RNA (shMYOC) in a MYOCP370L transgenic glaucoma mouse model (Tg-MYOCP370L) for the treatment of open-angle glaucoma (OAG) associated with MYOC mutations. METHODS: An AAV-DJ vector, selected for its high transduction efficiency and tropism for trabecular meshwork (TM), was used to deliver shMYOC via a transpupillary intravitreal approach in Tg-MYOCP370L mice. Post-treatment evaluations included myocilin accumulation, ER stress marker expression, intraocular pressure (IOP), aqueous humor outflow facility, retinal ganglion cell (RGC) survival, and visual function. RESULTS: AAV-DJ-shMYOC markedly reduced myocilin accumulation and ER stress markers in TM cells in vivo, effectively preventing age-dependent IOP elevation, preserving aqueous humor outflow facility, and maintaining RGC survival and visual function in young Tg-MYOCP370L mice. In aged Tg-MYOCP370L mice, AAV-DJ-mediated MYOC silencing similarly lowered IOP and improved outflow facility. CONCLUSIONS: AAV-DJ-mediated MYOC silencing effectively alleviated glaucomatous pathology in Tg-MYOCP370L mice, highlighting its potential as a gene therapy strategy for myocilin-associated glaucoma.