Emerging Treatments for Leber's Hereditary Optic Neuropathy and Other Genetic Causes of Visual Loss

Abstract

Leber's hereditary optic neuropathy (LHON) and other genetic causes of visual loss are important clinical entities that can cause profound visual loss. To date, therapeutic options have been quite limited, but insights into the genetic basis of these diseases and advances in the ability to deliver effective and safe gene therapy have opened the door for new therapeutics that may revolutionize the approach to treating these conditions. This article reviews emerging gene therapies of LHON and other inherited ophthalmological diseases, addressing the technical, clinical, and ethical challenges that researchers and clinicians will encounter as new treatments become available for these conditions.

Keywords

Leber’s hereditary optic neuropathy - LHON - gene therapy

• References

• 1 Leber T. Ueber hereditäre und congenital-angelegte Sehnervenleiden. Graefe's Arhiv für Ophthalmologie 1871; 17 (02) 249-291
• 2 Wallace DC, Singh G, Lott MT. , et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242 (4884): 1427-1430
• 3 Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1991; 48 (06) 1147-1153
• 4 Mackey D, Howell N. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet 1992; 51 (06) 1218-1228
• 5 Hwang TJ, Karanjia R, Moraes-Filho MN. , et al. Natural history of conversion of Leber's hereditary optic neuropathy: a prospective case series. Ophthalmology 2017; 124 (06) 843-850
• 6 Balducci N, Savini G, Cascavilla ML. , et al. Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy. Br J Ophthalmol 2016; 100 (09) 1232-1237
• 7 Newman NJ, Biousse V, David R. , et al. Prophylaxis for second eye involvement in Leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol 2005; 140 (03) 407-415
• 8 Newman NJ. Treatment of Leber hereditary optic neuropathy. Brain 2011; 134 (Pt 9): 2447-2450
• 9 Koilkonda RD, Guy J. Leber's hereditary optic neuropathy-gene therapy: from benchtop to bedside. J Ophthalmol 2011; 2011 (07) 179412-179416
• 10 Klopstock T, Yu-Wai-Man P, Dimitriadis K. , et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain 2011; 134 (Pt 9): 2677-2686
• 11 Sadun AA, Chicani CF, Ross-Cisneros FN. , et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol 2012; 69 (03) 331-338
• 12 Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995; 118 (Pt 2): 319-337
• 13 Lam BL, Feuer WJ, Schiffman JC. , et al. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol 2014; 132 (04) 428-436
• 14 Shi H, Gao J, Pei H. , et al. Adeno-associated virus-mediated gene delivery of the human ND4 complex I subunit in rabbit eyes. Clin Exp Ophthalmol 2012; 40 (09) 888-894
• 15 Yang S, Ma S-Q, Wan X. , et al. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy. EBioMedicine 2016; 10: 258-268
• 16 Guy J, Qi X, Koilkonda RD. , et al. Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Invest Ophthalmol Vis Sci 2009; 50 (09) 4205-4214
• 17 Koilkonda RD, Yu H, Chou T-H. , et al. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol 2014; 132 (04) 409-420
• 18 Feuer WJ, Schiffman JC, Davis JL. , et al. Gene therapy for leber hereditary optic neuropathy: initial results. Ophthalmology 2016; 123 (03) 558-570
• 19 Guy J, Feuer WJ, Davis JL. , et al. Gene therapy for Leber hereditary optic neuropathy: low- and medium-dose visual results. Ophthalmology 2017; 124 (11) 1621-1634
• 20 Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol 2017; 101 (09) 1147-1154
• 21 Kumaran N, Pennesi ME, Yang P. , et al. Leber congenital amaurosis/early-onset severe retinal dystrophy overview. In: Adam MP, Ardinger HH, Pagon RA. , et al., eds. GeneReviews. Seattle, WA: University of Washington; 1993
• 22 Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A 1998; 95 (06) 3088-3093
• 23 Bainbridge JWB, Smith AJ, Barker SS. , et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med 2008; 358 (21) 2231-2239
• 24 Hauswirth WW, Aleman TS, Kaushal S. , et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008; 19 (10) 979-990
• 25 Maguire AM, Simonelli F, Pierce EA. , et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med 2008; 358 (21) 2240-2248
• 26 Weleber RG, Pennesi ME, Wilson DJ. , et al. Results at 2 years after gene therapy for RPE65-deficient Leber congenital amaurosis and severe early-childhood-onset retinal dystrophy. Ophthalmology 2016; 123 (07) 1606-1620
• 27 Le Meur G, Lebranchu P, Billaud F. , et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis. Mol Ther 2018; 26 (01) 256-268
• 28 Russell S, Bennett J, Wellman JA. , et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 2017; 390 (10097): 849-860
• 29 Chung DC, McCague S, Yu Z-F. , et al. Novel mobility test to assess functional vision in patients with inherited retinal dystrophies. Clin Exp Ophthalmol 2018; 46 (03) 247-259
• 30 MacLaren RE, Groppe M, Barnard AR. , et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014; 383 (9923): 1129-1137
• 31 Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res 2014; 43: 108-128
• 32 Dalkara D, Goureau O, Marazova K, Sahel J-A. Let there be light: gene and cell therapy for blindness. Hum Gene Ther 2016; 27 (02) 134-147
• 33 Trapani I, Colella P, Sommella A. , et al. Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol Med 2014; 6 (02) 194-211
• 34 Maddalena A, Tornabene P, Tiberi P. , et al. Triple vectors expand AAV transfer capacity in the retina. Mol Ther 2018; 26 (02) 524-541
• 35 Maddalena A, Dell'Aquila F, Giovannelli P. , et al. High-throughput screening identifies kinase inhibitors that increase dual adeno-associated viral vector transduction in vitro and in mouse retina. Hum Gene Ther 2018; 29 (08) 886-901
• 36 Terrell D, Comander J. Current stem-cell approaches for the treatment of inherited retinal degenerations. Semin Ophthalmol 2019; 34 (04) 287-292
• 37 Schwartz SD, Regillo CD, Lam BL. , et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 2015; 385 (9967): 509-516
• 38 Boudreault K, Justus S, Lee W, Mahajan VB, Tsang SH. Complication of autologous stem cell transplantation in retinitis pigmentosa. JAMA Ophthalmol 2016; 134 (06) 711-712
• 39 Kim JY, You YS, Kim SH, Kwon OW. Epiretinal membrane formation after intravitreal autologous stem cell implantation in a retinitis pigmentosa patient. Retin Cases Brief Rep 2017; 11 (03) 227-231