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Review Article

Gene-Based Therapies for Leber Hereditary Optic Neuropathy. Hype or Hope?

Mackey, David A. FRANZCO; Kearns, Lisa S. BOrth; Hewitt, Alex W. FRANZCO

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Asia-Pacific Journal of Ophthalmology: July/August 2016 - Volume 5 - Issue 4 - p 253-255
doi: 10.1097/APO.0000000000000220
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In 2015, the initial results of a gene therapy trial for Leber hereditary optic neuropathy (LHON) were published.1 This exciting report of the initial outcome of a phase 1 trial is the culmination of over a decade of work by John Guy’s team at the Bascom Palmer Eye Institute. Leber hereditary optic neuropathy is such a devastating disease that any progress toward a treatment is very welcome. However, as with the earlier animal experiments that preceded this trial, we do not yet have proof that this treatment will restore vision loss in people with LHON or if it will prevent vision loss in the other eye. Phase 2 and phase 3 trials are required to prove the actual effect. A phase 1 trial is a safety study, and thus older patients are often invited to participate, if it is believed there may be some possibility of benefit. Five legally blind individuals aged between 35 and 55 years participated in the study. All participants had the most severe mutation for LHON [guanine to adenine substitution at position 11778 of the mitochondrial genome (mtDNA)], which is also the most common and least likely to be associated with spontaneous recovery. Four male participants had lost vision 3 to 20 years earlier. Most participants in this late stage would have marked optic atrophy and recovery would be unlikely. However, as recovery has been seen (though very rarely) in untreated LHON participants several years after vision loss, there is still a chance for these participants to recover some vision beyond the 180 days of the current study. The only female trial participant had lost vision less than 12 months earlier and it is important to note that, from extensive natural history data, a recent case is more likely to recover vision spontaneously. Interestingly, the female participant improved by 17 letters in the treated eye, but she also improved by 7 letters in the untreated eye. The question must be asked: is this the result of the gene therapy working or is it just the natural history of disease? Other research groups are preparing similar gene therapy trials for LHON, and the effectiveness of these slightly different approaches will require equal attention.2

Leber hereditary optic neuropathy is an uncommon disorder that causes devastating central vision loss in otherwise healthy young adults. It predominantly affects men in their 20s, but the disease can arise at any age, and around one fifth of affected people are female. The visual impairment is similar to that of severe age-related macular degeneration, so although most affected cases are legally blind, they have relatively good peripheral vision and rarely use guide dogs or canes. Maternal inheritance studies led to the identification of mutations in the mtDNA at positions 11,778, 3460, and 14,484.3 The majority of mutation carriers never lose vision, and the reason for this incomplete penetrance and male predominance remains to be explained.


There has been more than a century of failed “cures” for LHON. Treatments in Theodor Leber’s time4 included bloodletting with leeches and cuppings. The overabundance of circulating blood in the patient was thought to be responsible for dilated blood vessels compressing the optic nerve or retina. In addition, Leber tried electrical treatment with a constant current from an electrode placed on the posterior aspect of the neck and an eye cup electrode over the closed eye. The constant galvanic current was used for some minutes with reversals of polarity and repeated daily for 1 or 2 weeks. The “treatments” for syphilis were also widely used for LHON: potassium iodide solution, potassium or mercury salts and quinine, strychnine injected into the temple, or irrigation of the eyes with silver nitrate. In the mid-20th century, steroids and hydroxycobalamin5 were used without obvious benefit, although no trials were conducted.6 Brimonidine had been proposed to be neuroprotective in glaucoma. An open-label, nonrandomized multicenter trial of topical brimonidine 0.15% as prophylaxis for second eye involvement in LHON found no benefit.7 After the mitochondrial genetic link in LHON was identified, a huge cocktail of antioxidant and mitochondrial vitamins including CoQ10 were used. A drug similar to CoQ10—idebenone—was investigated after it was reported to induce remission in a 10-year-old boy with LHON due to the 11778 mutation.8 A large randomized trial, Rescue of Hereditary Optic Disease Outpatient Study, enrolled 85 patients with a confirmed primary mtDNA mutation and with disease duration of up to 5 years.9 Patients treated with idebenone (900 mg/d) experienced no adverse drug reactions over 24 weeks. This trial failed to show benefit for idebenone in terms of the prespecified primary endpoint (best recovery of visual acuity at week 24), but there was a positive trend toward visual improvement in the secondary endpoints. A post hoc analysis of the trial data also indicated that patients with discordant visual acuities, and hence at highest risk of further deterioration in the least affected eye, were more likely to benefit from treatment with idebenone.10 Thus, does idebenone miraculously restore vision? The answer is no, but it may result in slightly better (less reduced) long-term visual acuity. Specific endpoints and an adequate number of study participants meeting entry criteria are critical to answering these important questions and are a challenge with uncommon diseases, such as LHON. To enrol enough of the “most suitable patients” at the right stage of disease, we may need to recruit from the whole world. The age of LHON patients influences their chance of recovery. Children are very likely to spontaneously recover some vision, and this must be taken into account if children are included in a trial.11

Patients’ performance on visual acuity testing (the most common test done in ophthalmology) fluctuates from day to day. Two lines of improvement has been the criterion standard for most clinical trials12 but is unrealistic for many gene therapy trials. Other metrics for slowly progressing retinal diseases have required the development of other tools, such as vision-guided ambulatory navigation,13 as used in RPE65 trials for Leber congenital amaurosis, or microperimetry, as used in choroideremia trials.14 A miraculous cure and recovery of vision to normal levels in patients with LHON of long duration is not evident from gene therapy or idebenone. To establish if vision is a few lines better has been a huge problem with idebenone and may prove to be equally difficult for gene therapy trials.


When should LHON patients receive gene therapy? We would expect to see trials evolve from including patients with longstanding blindness to recruiting acute patients with recent loss of vision or, ideally, the patients whose 1 eye has dramatically lost vision and the good eye is minimally affected, which was the group used in the brimonidine study.7 Given that we see spontaneous recovery, any trials must be placebo-controlled. Even if the treatment of affected patients is ineffective, this does not mean that preventive treatment would not work. Most members of large LHON families seem to have 100% mutant mtDNA regardless of whether they lose vision. Some smaller LHON pedigrees have members with mtDNA heteroplasmy, a mixture of mutant and wild-type mitochondria. The nuclear-targeted gene therapy trials do not actually change mitochondrial DNA, but at a protein level, there is “heteroplasmy” of the ND4 proteins, mutant and genetic-engineered. It seems that heteroplasmic individuals are less likely to lose vision. Thus, a trial of gene therapy for as yet unaffected high-risk individuals would seem appropriate. Table 1 lists the different timing for any LHON treatment.

What Is the Besting Timing of Any LHON Treatment?

The scenarios of treatment will need to have careful evaluations of study endpoints. If treatment is proposed for people with loss of vision in 1 eye, then we need to confirm the true rate of bilateral involvement. Although it is near 100%, there are people who seem to have unilateral involvement. In addition, the timing of second eye involvement is thought to be within a year, but how long would we need to follow treated patients? Even with a perfectly designed study, it is tricky to recruit patients at this stage (the window between the first and second eye losing vision).7

To prevent vision loss in high-risk family members, such as unaffected male siblings in early adulthood, we must have accurate information on the risk of vision loss in family members. The literature repeats a risk of 50%, but this is probably a presumed “Mendelian” risk matching that for autosomal dominant disease, which is not actually based on true evidence. Researchers who have only examined small pedigrees risk an ascertainment bias, whereas larger pedigrees show that there seem to be high- and low-risk branches within pedigrees.15 In addition, the lifetime risk of vision loss from LHON in those larger families that have been studied seems much lower. Fewer than 20% of adult male mutation carriers in large Australian LHON pedigrees lose vision.16 This work was based on extensive genealogical identification of all siblings throughout the pedigrees. Affected cases talk about their affected siblings more than their unaffected siblings, and often pedigrees are incomplete, missing many unaffected uncles. Extensive pedigrees in the Netherlands and Denmark also suggest a lower than 50% risk of vision loss (30%).17 Any study of prevention of vision loss in high-risk individuals that uses a 50% risk of loss of vision may be significantly underpowered if the true risk is 20%. In heteroplasmic families, the risk will be even lower. The overinflated risk of vision loss in LHON mutation carriers may lead to patients taking more drastic treatment risks to prevent vision loss. Moreover, the risk of vision loss seems to drop over time, as observed in a large Tasmanian family18 and a large Italian-Brazilian family.19


Although we may see recovery of vision in LHON patients, do we know if this will be sustained? In some LHON patients with the 14,484 mutation who have recovered vision, a gradual decline in visual acuity has been observed (personal observation). There are scant published data on this.


Erasmus is attributed with the axiom “Prevention is better than cure.” Antenatal sex selection avoiding sons in favor of daughters is one straightforward method to reduce the risk of LHON in families. Although this reduces the child’s risk (girls have a lower risk for losing vision than boys), having a daughter passes on the same dilemma of worrying about offspring risk a generation later. The most definitive way to prevent LHON would be to replace the mutant mitochondria at conception using “3-parent embryos.”20 In addition to the parents’ germ line tissues, a donor egg provides “healthy mitochondria.” Although approved in the United Kingdom, the long-term safety is completely unknown. Other simpler possibilities include donor eggs or, to partly match the parents’ genetic mix, the egg of the father’s sister and sperm of the mother’s brother could be used.


A diagnosis of LHON is a particularly devastating situation for a family. Clinical trials can bring hope, but when a patient finds he is not eligible, he may relive the devastation. It is unethical to bankrupt a family in search of a miracle cure, leaving them with no resources to fund adaptive technologies that have great potential to improve quality of life. Would a driverless car be a better expenditure of money than a treatment that just brings a line or 2 of improvement in vision but not enough to get a driver’s license?

Although new treatments bring promise, an affected person can end up living in limbo waiting for a miracle cure rather than getting on with his life. It is vital that clinicians and counselors guide patients between hope and hype in trials of potential future treatments. There is a key role for patient support groups to provide updated advice and resources to educate patients about available clinical trials. We need to distinguish proper clinical trials from quackery (some of which still get registered as a clinical trial) and encourage patients to participate.21 They must ask the following: Is the trial registered as a clinical trial? What ethics/institutional review board approval is in place and from where? How is the trial funded, by what organization or company? What phase of the study am I to be enrolled in and what are the results of preliminary studies to date? If patients in the Asia-Pacific region choose to participate in North American and European clinical trials, then they may need to cover the travel and accommodation costs of monthly visits for a year or more. This could easily amount to more than US$50,000 a year for a patient and a companion. However, those patients who participate in trials may be spared the later expense of gene therapies that may cost US$1 million. Finally, as succinctly outlined by Charo, “It will take a concerted effort by researchers, journal editors, companies, investors, and the media to find the fine line between hope and hype and to keep explaining why the best way to find safe, effective cures is through the careful steps of clinical trials and treatment monitoring.”22


Leber hereditary optic neuropathy gene therapy trials offer hope for a treatment to reverse acute vision loss. Rigorously conducted trials with well-defined endpoints must be supported as a global effort. However, interpretation of the results must be realistic for patients and their families. Restoration of vision from counting fingers to 6/6 may be worth a million dollar treatment, but if there is minimal visual improvement, then diversion of funds may jeopardize financing more definitive future research.


1. Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology. 2016;123:558–570.
2. Cwerman-Thibault H, Augustin S, Lechauve C, et al. Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Mol Ther Methods Clin Dev. 2015;2:15003.
3. Mackey DA, Oostra RJ, Rosenberg T, et al. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. 1996;59:481–485.
4. Piotrowska A, Korwin M, Bartnik E, et al. Leber hereditary optic neuropathy—historical report in comparison with the current knowledge. Gene. 2015;555:41–49.
5. Foulds WS, Cant JS, Chisholm IA, et al. Hydroxocobalamin in the treatment of Leber’s hereditary optic atrophy. Lancet. 1968;1:896–897.
6. Yu-Wai-Man P, Votruba M, Moore AT, et al. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). 2014;28:521–537.
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;140:407–415.
8. Mashima Y, Hiida Y, Oguchi Y. Remission of Leber’s hereditary optic neuropathy with idebenone. Lancet. 1992;340:368–369.
9. 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.
10. Klopstock T, Metz G, Yu-Wai-Man P, et al. Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain. 2013;136(Pt 2):e230.
11. Barboni P, Savini G, Valentino ML, et al. Leber’s hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci. 2006;47:5303–5309.
12. Patel PJ, Chen FK, Rubin GS, et al. Intersession repeatability of contrast sensitivity scores in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50:2621–2625.
13. Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372:1887–1897.
14. 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;383:1129–1137.
15. Howell N, Mackey DA. Low-penetrance branches in matrilineal pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. 1998;63:1220–1224.
16. Mackey DA, Buttery RG. Leber hereditary optic neuropathy in Australia. Aust N Z J Ophthalmol. 1992;20:177–184.
17. Oostra RJ, Kemp S, Bolhuis PA, et al. No evidence for ‘skewed’ inactivation of the X-chromosome as cause of Leber’s hereditary optic neuropathy in female carriers. Hum Genet. 1996;97:500–505.
18. Mackey D, Howell N. Tobacco amblyopia. Am J Ophthalmol. 1994;117:817–819.
19. Sadun AA, Carelli V, Salomao SR, et al. A very large Brazilian pedigree with 11778 Leber’s hereditary optic neuropathy. Trans Am Ophthalmol Soc. 2002;100:169–178; discussion 78–79.
20. Falk MJ, Decherney A, Kahn JP. Mitochondrial replacement techniques—implications for the clinical community. N Engl J Med. 2016;374:1103–1106.
21. Ross JS, Mulvey GK, Hines EM, et al. Trial publication after registration in ClinicalTrials.Gov: a cross-sectional analysis. PLoS Med. 2009;6:e1000144.
22. Charo RA. On the road (to a cure?)—stem-cell tourism and lessons for gene editing. N Engl J Med. 2016;374:901–903.

LHON; AAV gene therapy

© 2016 by Asia Pacific Academy of Ophthalmology