Gene Therapy for Leber Hereditary Optic Neuropathy: Is Vision Truly RESCUED?

Over 3 decades ago, Leber hereditary optic neuropathy (LHON) was the first condition found to be associated with a mitochondrial DNA mutation, and now remarkably it is inaugural disease undergo gene therapy trials. In this issue, Newman et al1Newman N.J. Yu-Wai-Man P. Carelli V. al.Efficacy safety of intravitreal for treated within 6 months onset.Ophthalmology. 2021; 128: 649-660Abstract Full Text PDF Scopus (14) Google Scholar (see page 649) report findings RESCUE, multicenter, randomized, double-masked, sham-controlled, phase clinical trial evaluating efficacy single injection rAAV2/2-ND4 in 1 eye patients m.11778G>A mutation onset vision loss an attempt “rescuing” loss. The primary end point improved best-corrected visual acuity (BCVA) compared sham at 48 weeks not met, both eyes deteriorating 19 20 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively. However, 96 weeks, average BCVA unexpectedly by 9 10 ETDRS letters eyes, Although slightly worse than baseline (−9 −10 respectively), statistically significantly better nadir loss, improvement +26 +23 respectively (P < 0.0001), which generated hypothesis potential bilateral unilateral injection. results RESCUE come on heels REVERSE trial, executed same excellent international collaborative team identical methodology, except treatment done 12 after loss.2Yu-Wai-Man al.Bilateral neuropathy.Sci Transl Med. 2020; 12: eaaz7423Crossref PubMed (28) also showed surprisingly, later resulted outcomes authors describe as “counterintuitive.” This very fitting word because expectation that earlier would prevent from dropping its natural lead outcomes. failed “rescue” addition, received before but unfortunately still dropped 20/800 improving 20/400 weeks. prevented, remains unclear what led trials despite treatment. Bilateral LHON has been noted 2 other allotopic trials.3Yuan J. Zhang Y. Liu H. al.Seven-year follow-up Leber's neuropathy.Ophthalmology. 127: 1125-1127Abstract (17) Scholar,4Guy Feuer W.J. Davis J.L. al.Gene neuropathy: low- medium-dose results.Ophthalmology. 2017; 124: 1621-1634Abstract (105) Follow-up studies Cynomolgus monkeys have suggested viral expression provided plausibility treatment.2Yu-Wai-Man addition possible contralateral spread, else could explain fellow improvement: motivated patient/placebo effect or some bias? Is history disease? Arguably most detailed study comes Lam al.5Lam B.L. Schiffman J.C. al.Trial points G11778A preparation trial.JAMA Ophthalmol. 2014; 132: 428-436Crossref (62) They only 18% spontaneously > 15 letters.5Lam At glance, seems less reported trials; however, al5Lam enrollment rather nadir. Among 34 18 months, 17 (50%) (Bill Feuer, MS, personal communication, Bascom Palmer Eye Institute, Miami, FL, January 2021), more closely mirrors trial. Ultimately, placebo-controlled patient randomized versus true (no either eye) may required answer question LHON. Another future therapy, envisioned late Dr. John Guy, direct targeting expression. With being identified, if became remedied therapy. we ways go, it’s exciting field ophthalmology leading way rescuing disease. Efficacy Safety Intravitreal Gene Therapy Hereditary Optic Neuropathy Treated Months Disease OnsetOphthalmologyVol. 128Issue 5PreviewTo evaluate subjects (LHON). Full-Text Open Access