Mol Ther. 2023 Apr 3:S1525-0016(23)00195-8. doi: 10.1016/j.ymthe.2023.03.035. Online ahead of print.
Lenadogene nolparvovec (GS010) was developed to treat a point mutation in mitochondrial ND4 that causes Leber hereditary optic neuropathy. Lenadogene nolparvovec delivers human cDNA encoding wild-type ND4 packaged into an rAAV2/2 vector that transduces retinal ganglion cells, to induce allotopic expression of hybrid mitochondrial ND4. Lenadogene nolparvovec clinical trials improved best-corrected visual acuity (BCVA) up to 5 years post treatment. Interestingly, unilateral treatment improved BCVA bilaterally. Subsequent studies revealed lenadogene nolparvovec DNA in visual tissues contralateral to the injected eye, suggesting migration. Here we tested whether unilateral intraocular pressure (IOP) elevation could influence transfer of viral ND4 RNA in contralateral tissues following GS010 delivery to the IOP-elevated eye and probed a potential mechanism mediating translocation in mice. We found IOP elevation enhanced viral ND4 RNA transcripts in contralateral visual tissues, including retinas. Using conditional transgenic mice, we depleted astrocytic gap junction connexin 43 (Cx43), required for distant redistribution of metabolic resources between astrocytes during stress. Following unilateral IOP elevation and GS010 injection, Cx43 knockdown eradicated ND4 RNA transcript detection in contralateral retinal tissues, while transcript was still detectable in optic nerves. Overall, our study indicates long-range migration of GS010 product to contralateral visual tissues is enhanced by Cx43-linked astrocyte networks.