The ins and outs of gene therapy for inherited optic neuropathies


A look at what’s in the therapeutic delivery pipeline for these disorders.

The ins and outs of gene therapy for inherited optic neuropathies

(Image courtesy ©Fantastic /

Inherited optic neuropathies (IONs) are a group of disorders that result in degeneration of the retinal ganglion cells (RGCs) and optic atrophy,1 affecting about 1 in 10,000 individuals in the general population. They represent an important cause of visual impairment and reduced quality of life in children and young adults. There are currently no effective treatments for most IONs.

However, the rapid pace of technological innovation within the field of gene therapy and editing has accelerated the therapeutic delivery pipeline for these inherited forms of blindness.

The ins and outs of gene therapy for inherited optic neuropathies

This article will provide an overview of recent developments in gene therapy for IONs and highlight some of the challenges that are unique to these disorders.

The clinical spectrum

The two most common IONs encountered in clinical practice are autosomal dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON).1 Historically, the diagnosis of both conditions was based on clinical characteristics including the patient’s demographic features, the pattern of vision loss and the mode of inheritance. It is now recognised that both conditions are genetically heterogeneous with multiple genetic variants causing the same clinical presentation.

DOA has an estimated prevalence of 1 in 25,000.2 The disease is highly penetrant with estimates of ~70% (43-100%) reported.3 Typically, patients develop a bilateral optic atrophy that begins in the first two decades of life, resulting in progressive visual acuity and field loss that deteriorates to legal blindness in later life. Clinical management is currently limited to low-vision aids/rehabilitation, supportive care, and genetic/reproductive counselling.

LHON has an estimated prevalence between 1 in 30,000 to 50,000 in Northern Europe.4 In contrast to DOA, most individuals who carry a genetic mutation associated with LHON remain asymptomatic. Men who carry a LHON mitochondrial DNA (mtDNA) mutation are at greater risk of developing vision loss compared to women (17.5% vs 5.4% respectively).5 Patients develop severe bilateral sequential or simultaneous vision loss (peak age at onset 15 to 35 years), characterised by a dense central or caecocentral scotoma and visual acuity worse than 3/60 (logMAR 1.3). Idebenone (Raxone) is the only treatment for LHON authorised by the European Medicines Agency (EMA), with several clinical trials and real-world observational studies demonstrating benefit in a subgroup of treated patients.1

Although most patients with an ION experience isolated visual loss, some can develop more severe neurological features. Around 20% of patients with DOA have evidence of extraocular features, which typically includes a sensorineural hearing loss, peripheral neuropathy, and ataxia. Similarly, individuals affected by LHON can develop extraocular manifestations including movement disorders or a multiple sclerosis-like syndrome (so-called Harding disease). Some multisystemic disorders, such as Wolfram Syndrome and many of the primary mtDNA disorders, can also manifest with a DOA- or LHON-like vision loss and optic atrophy, and therefore, could be considered as part of the clinical spectrum of IONs.

Autosomal dominant optic atrophy

The most common causative gene in DOA is OPA1 (3q21), responsible for over 60% of DOA cases [6] [Figure 1]. OPA1 is thought to be critical in regulating mitochondrial fusion, bioenergetics, and cell death (apoptosis). OPA1 is expressed in all cells in the body, but it is enriched in neural tissues and highly metabolically active organs such as the heart and liver. Why variants in OPA1 result specifically in loss of RGCs and not other cell types remains a subject of debate, but may be due to the unique structural and bioenergetic demands of RGCs, and their particular gene expression pattern.

The ins and outs of gene therapy for inherited optic neuropathies

Despite the challenges of developing genetic therapies for a gene which has many pathogenic variants, DOA remains an exciting target for gene therapies because it is autosomal (autosomal DNA is easier to edit than mitochondrial DNA). Normally it only affects one organ which has an easy drug-delivery route (intravitreal injection); and has a relatively gradual disease course, meaning there is hypothetically a large therapeutic window.

There are two broad strategies for gene therapy for DOA [Figure 1]. The first is gene editing and the second is modification of genetic expression by altering gene transcription. Gene editing is theoretically the most direct treatment of DOA involving correction of the disease-causing OPA1 variant. However, OPA1 is a relatively large gene (over 90kb) and a complete replacement gene cannot be packaged into an adeno-associated viral vector (AAV). Gene editing strategies such as CRISPR-Cas9 have been used to correct OPA1 variants in vitro, but the components of the system are again too large for an AAV vector and there remains concerns regarding low editing efficiency, off-target effects, and a potential risk of cell toxicity secondary to supraphysiological expression of OPA1.

An alternative approach which addresses these concerns involves the use of transcriptional modifiers such as antisense oligonucleotides (ASOs). ASOs are short portions of single-stranded nucleotides that can bind and modulate expression of mRNA or pre-mRNA. Stoke Therapeutics (Bedford, Massachusetts, USA) is currently investigating an ASO that uses an upregulation approach by stoking protein production from the functional copy of the OPA1 gene.

Another company, PYC Therapeutics (Perth, Australia) is trialling a related method for modulating gene expression, called a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), to restore levels of OPA1 expression. Transcriptional modification remains the most active area of translational research and a number of these technologies are entering early stage clinical trials. It remains to be seen if the preclinical data of increased OPA1 expression results in a clinically meaningful attenuation of RGC loss and visual benefit.

Leber hereditary optic neuropathy

Three primary point mutations in the mtDNA (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6) are responsible for ~90% of LHON cases globally [2]. These mutations all involve genes encoding subunits of complex I – the first enzyme of the mitochondrial respiratory chain. In LHON, defective mitochondrial oxidative phosphorylation precipitates a bioenergetic crisis; oxidative damage to DNA, proteins, and lipids secondary to elevated levels of toxic reactive oxygen species; and release of signalling factors that trigger RGC apoptosis. Like DOA, most cases of LHON appear to cause selective degeneration of RGCs, especially the relatively smaller fibres that make up the papillomacular bundle.1

Due to the double mitochondrial membrane, conventional AAV vectors are prevented from entering the mitochondria or transferring exogenous genetic material into the mitochondrial matrix. Instead, gene therapy in LHON has utilised the technique of allotopic expression (Figure 2).

The ins and outs of gene therapy for inherited optic neuropathies

Several clinical trials have now been conducted for the m.11778G>A mutation in MT-ND4, the most prevalent mutation causing LHON accounting for 60-90% of cases depending on the population surveyed. Three separate groups (Bascom Palmer Eye Institute, Miami, Florida, USA; Huazhong University of Science and Technology and Neurophth Therapeutics, Wuhan, China; and GenSight Biologics, Paris, France) have independently conducted gene therapy clinical trials. Although differences in treatment efficacy have been reported, possibly related to variations in study and vector design, gene therapy was found to be well tolerated across all studies, with transient ocular inflammation the main side effect identified.

GenSight Biologics have completed and published the results of their Phase III trials (RESCUE (NCT02652767), REVERSE (NCT02652780) and REFLECT (NCT03293524)).7,8,9 Eyes treated with LUMEVOQ within 12 months onset of vision loss demonstrated a progressive and sustained improvement in best-corrected visual acuity (BCVA) from 12 to 51.5 months after onset of vision loss. Compared with a natural history cohort, there was a statistically and clinically relevant difference in BCVA (improvement in 0.33 logMAR) in favour of treated eyes at 48 months after onset of vision loss.10 GenSight Biologics have submitted a marketing authorisation application for LUMEVOQ to the European Medicines Agency (EMA) in September 2020 and an opinion from the EMA’s Committee for Medicinal Products for Human Use is currently awaited.

Other gene therapy strategies currently under pre-clinical investigation are mtDNA heteroplasmy shifting and mitochondrial base editing. Mutant mtDNA molecules often exist in conjunction with the wild-type mtDNA species, a situation known as heteroplasmy. Mitochondrially-targeted zinc finger nucleases and transcription activator-like effector nucleases (TALENs) have been used successfully in vitro and in animal models to induce heteroplasmic shift by favouring the replication of wild-type mtDNA molecules.11 However, this strategy has limited applicability for LHON as most carriers are homoplasmic mutant. Another genomic approach that is being considered is mitochondrial base editing using a non-CRISPR-based mtDNA editing tools, including Ddda-derived cytosine base editor (DdCBE).12 The platform is still in its infancy and it is currently limited to C•G-to-T•A editing, making it a viable strategy for the m.14484T>C mutation in MT-ND6.


Important questions remain regarding the use of genetic therapies in the treatment of IONs and the ideal therapeutic window. Knowing who to treat is critically important as treatments are likely to be expensive requiring sometimes difficult decisions to be made by medical experts and policy makers. A mutation-specific gene therapy treatment is unlikely to be available for all patients. Mutation-independent gene therapies that aim to improve mitochondrial respiration, reduce mitochondrial stress, inhibit or delay RGC apoptosis, and promote RGC survival are attractive as they can potentially be utilised in all patients with an ION in combination with other neuroprotective therapies, if available. Specific genes under pre-clinical investigation that have been shown to improve defective mitochondrial function and/or increase RGC survival include SOD2, NRF2, and a novel transgene coding brainderived neurotrophic factor (BDNF) and tropomyosin-related receptor-B (TrKB).13

Knowing when to treat is also important given that some genetic therapies, for example, ASOs, have a relatively short half-life and so timing a treatment or its frequency is likely to be critical in maximising the therapeutic effect. DOA is a highly penetrant disease with a relatively gradual disease course, meaning there is hypothetically a large therapeutic window for all patients to be treated. Although gene therapy utilising allotopic expression appears to be effective for patients with LHON treated within one year of onset of vision loss, the effect of gene therapy for patients with more chronic disease needs to be evaluated further. A better understanding of the natural history of IONs as well as prognostic factors may help to stratify LHON carriers at highest risk of vision loss for prophylactic treatment when such an option becomes available.

Another consideration is the cost of these treatments with Luxturna for RPE65 Leber congenital amaurosis, the only licensed gene therapy for an inherited eye disease, priced at around USD $850,000 per treatment.14 This cost reflects the expense of developing genetic therapies as well as the high-failure rate following clinical evaluation. Given that IONs are rare conditions and that a potential therapy may not be appropriate for all patients, it is important to consider how the provision of these treatments can be financially viable, particularly in countries with less well-resourced healthcare systems.


Genetic therapies hold promise for IONs with advances in gene delivery systems and gene editing technology having facilitated the development of innovative therapies over the past decade. Given the rarity of IONs and the costs associated with the development of gene therapy products, increasing effort is being directed toward strategies that are mutation-independent. With the number of therapies on the horizon for IONs, access to rapid genetic testing becomes even more important to establish the molecular diagnosis, aid visual prognostication and help to better understand genotype-phenotype correlations.

Dr Benson S. Chen, MBChB, MSc, FRACP
Dr Chen is a clinical research fellow and honorary clinical fellow, John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, United Kingdom.
Dr Joshua P. Harvey, MA, BM BCh, Pg Cert, FRCOphth
Dr Harvey is a clinical research training fellow and honorary research fellow,
Moorfields Eye Hospital NHS Foundation Trust, London, and Institute of Ophthalmology, University College London, London, United Kingdom.
Prof. Patrick Yu Wai-Man, BMedSci, MBBS, PhD, FRCPath, FRCOphth
Dr Yu Wai-Man is professor of ophthalmology, John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; and Institute of Ophthalmology, University College London, London, United Kingdom.
He is a consultant for Chiesi, GenSight Biologics, Stoke Therapeutics and Transine Therapeutics. The other authors do not have any relevant disclosures.
  1. Newman, N.J., Yu-Wai-Man, P., Biousse, V. et al. Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management. Lancet Neurol. 2022:S1474-4422(22)00174-0.
  2. Yu-Wai-Man, P., Griffiths, P.G., Burke, A. et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117:1538-46.
  3. Lenaers, G., Hamel, C., Delettre, C. et al. Dominant optic atrophy. Orphanet J Rare Dis. 2012;7:46.
  4. Chen, B.S., Yu-Wai-Man, P. From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy. Cold Spring Harb Perspect Med. 2022; 12:a041282.
  5. Lopez Sanchez, M.I.G., Kearns, L.S., Staffieri, S.E. et al. Establishing risk of vision loss in Leber hereditary optic neuropathy. Am J Hum Genet. 2021;108:2159-70.
  6. Yu-Wai-Man, P., Chinnery, P.F. Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. Ophthalmology. 2013;120:1712.
  7. Yu-Wai-Man, P., Newman, N.J., Carelli, V. et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. 2020;12:eaaz7423.
  8. Newman, N.J., Yu-Wai-Man, P., Carelli, V. et al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology. 2021;128:649-60.
  9. Newman, N.J., Yu-Wai-Man, P., Subramanian, P.S. et al. Randomised trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain. 2022;awac421.
  10. Newman, N.J., Yu-Wai-Man, P., Carelli, V. et al. Intravitreal gene therapy vs. natural history in patients with Leber hereditary optic neuropathy carrying the m.11778G>A ND4 mutation: Systematic review and indirect comparison. Front Neurol. 2021;12:662838.
  11. Jackson C.B., Turnbull, D.M., Minczuk, M. et al. Therapeutic manipulation of mtDNA heteroplasmy: A shifting perspective. Trends Mol Med. 2020;26:698-709.
  12. Mok, B.Y., de Moraes, M.H., Zeng, J. et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature. 2020;583:631-7.
  13. Osborne, A., Khatib, T.Z., Songra, L. et al. Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling. Cell Death Dis. 2018;9:1007.
  14. (February 16, 2022). How much does Luxturna cost? Retrieved October 14, 2022, from:
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