Factors determining the early beneficial effect of unilateral gene therapy in Leber's hereditary optic neuropathy patients carrying variant m.11778G>A.

Abstract

We read with interest the article by Liu et al. (2020) about factors determining improvement of visual acuity in Leber’s hereditary optic neuropathy (LHON) due to the variant m.11778G>A after unilateral gene therapy by intra-vitreous injection of the vector scAAV2. The authors concluded that latency between clinical onset and initiation of gene therapy and pretreatment best-corrected visual acuity were the strongest predictors of improvement in visual acuity in 149 LHON patients (Liu et al. 2020). The study has a number of shortcomings. The main shortcoming is that spontaneous recovery of visual acuity, as has been previously reported for the variant m.11778G>A (Leo-Kottler et al., 2000; Acaroğlu et al., 2001; Brown et al. 2001), was not considered. Including the possibility of spontaneous recovery may strongly alter the conclusions. If the maximal latency between clinical onset and starting therapy was 312 months, the patient with this latency must have had a particularly early-onset given a mean age at onset of 19 years (Liu et al. 2020). We should know when LHON in this, particularly, patient actually started. Permanent improvement after gene therapy with stable visual acuity was reported during multiple follow-ups. However, we should know the latency between injection and last follow-up to assess whether improvement was indeed a long-lasting effect. Knowing the long-term outcome of the treatment is crucial for assessing when re-injection is required. We should know whether the long-term outcome was different between group 1 and 2. It is conceivable that the therapeutic effect of unilateral gene therapy is related to heteroplasmy rates of the m.11778G>A variant or to mtDNA copy number. Thus, we should know whether heteroplasmy rates were obtained in all 149 included patients and whether the mtDNA copy number was determined. It would be interesting to know whether heteroplasmy rate and copy number varied between group 1 and 2. A further shortcoming is that the current medication the 149 patients were regularly taking was not provided. Potentially, anti-oxidants or cofactors may affect the course and outcome of LHON. In this line, risk factors which have been shown to trigger LHON or may have a modifying effect on the disease trajectory should be mentioned and discussed. Groups 1 and 2 should be investigated for any difference of these parameters. Since LHON may not only be a disease of the retinal ganglion cells but also of the brain, ears, endocrine organs, bone marrow, kidneys or the heart (Finsterer & Zarrouk-Mahjoub 2016), we should know how many of the included patients had LHON plus. Leber’s hereditary optic neuropathy (LHON) plus may have a completely different outcome than single system LHON. Thus, it is worthwhile to mention if the frequency of LHON and LHON plus were at variance between the two outcome groups. Secondary LHON mutations, haplotype and variants of unknown significance should be included in the assessment of the factors determining the outcome of the gene therapy. They should be assessed with regard to any difference between the two response groups. Family history is a prerequisite for assessment of the outcome and for genetic counselling. We should know how many of the 149 patients were first degree relatives and whether their outcome varied with regard to recovery of visual acuity. We should also know in how many of the patients the family history was positive for the disease and whether this varied between group 1 and 2. Overall, this interesting study carries a number of shortcomings which need to be addressed before drawing final conclusions. Risk factors, drugs, multisystem involvement, family history, mtDNA copy number and secondary LHON mutations need to be considered when assessing the outcome of a therapeutic intervention in LHON. Predictors of a beneficial effect of gene therapy in LHON may be completely different if these additional disease-modifying variables were considered.