Future Treatment of Leber Hereditary Optic Neuropathy

Ophthalmologists typically intervene once disease symptoms manifest, but, in some cases, the best visual outcomes are achieved by treating before any signs or symptoms appear. Indeed, this may be true for Leber Hereditary Optic Neuropathy (LHON). Emerging gene therapy techniques involving mitochondrial DNA editing in unaffected LHON carriers hold promise for optimizing visual outcomes. They have the potential to reduce disease penetrance and lower the conversion rate of carriers to symptomatic LHON; these interventions may also mitigate retinal ganglion cell loss if optic neuropathy eventually develops. In other words, a proactive approach could significantly improve the prognosis for individuals at risk of LHON (1).

Treating LHON is challenging due to its complex nature. Only a fraction of such genotype carriers will experience visual loss, with the specific triggers remaining undetermined. The window for effective treatment narrows early in the course of the condition as significant functional and anatomical deficits in retinal ganglion cells are present in both asymptomatic and symptomatic eyes. These deficits can be measured by pattern electroretinogram and OCT GCIPL thickness (2). Additionally, some LHON patients may experience spontaneous partial vision improvement months after the onset of visual loss, which can complicate the evaluation of treatment effectiveness (3).

One current clinically-tested gene therapy for LHON, with the G11778A mutation, involves indirectly delivering a normal ND4 protein to the mitochondria. This is done by introducing a nuclear-encoded version of the mitochondrial ND4 gene into the nucleus of retinal ganglion cells. The gene is then transcribed into mRNA, transported to the cytoplasm, and translated into the ND4 protein, which is subsequently transported to the mitochondria. Phase III clinical trials of this allotopic gene therapy have shown good safety and unexpectedly resulted in partial bilateral improvements in visual acuity. From the worst visual acuity recorded during the trial, treated eyes improved by nearly three lines, while untreated eyes improved by 2.5 lines. The final mean visual acuity levels after gene therapy were approximately 20/400 in both eyes.

Future clinical trials should include a randomized control group who do not receive gene therapy in either eye. This would better assess the treatment effect by determining whether the reported bilateral visual acuity changes are significantly different from the natural progression of the disease, sham treatments, or placebo treatments. Other promising LHON advanced medicine treatment strategies, which may offer superior outcomes compared to allotopic expression gene therapy, are currently in development. These approaches include direct DNA delivery into the mitochondria and mitochondrial base editing systems. And while using CRISPR systems with guide RNA to edit the mitochondrial genome presents significant challenges (mainly because the double membranes of the mitochondria block DNA entry), novel mitochondrial DNA editing strategies are being developed to overcome this obstacle.

Treating LHON genotype carriers before the onset of the disease using mitochondrial base editing techniques may yield solid visual outcomes. It is a preventative approach that could reduce disease penetrance by lowering the conversion rate of carriers to symptomatic LHON and minimize retinal ganglion cell loss if LHON does develop. However, there are several feasibility challenges to be considered first. LHON has a low carrier conversion rate, thus a clinical trial would need to be conducted over several years and require a large number of both treated and untreated participants. To assess the therapy's effectiveness, a composite outcome criterion would also need to be developed. This would incorporate the methodology of multiple primary endpoints, such as conversion rate and visual outcomes when LHON develops.

Though these challenges are daunting, the nature of diseases often requires innovative solutions that may seem impractical. Human ingenuity, however, knows no bounds – and it is time to think outside the box. Despite the obstacles, advancing our approach to treating LHON and similar conditions demands bold and creative strategies that push the boundaries of current medical and scientific capabilities.