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A “failed” clinical trial study showed improved treatment in LHON patients with results in both study and control eyes

Researchers based at the University of Cambridge, UK, have reported intriguing results from a Phase 3 trial for a gene therapy treatment of Leber hereditary optic neuropathy (LHON).  The key primary endpoint of the study provided a mean improvement in BCVA of −0.308 LogMAR (+15 ETDRS letters) for the study eye, compared with a mean improvement of −0.259 LogMAR (+13 ETDRS letters) in sham-treated eyes.  While the outcome clearly found that the endpoint was not met, the research has provided many more questions than answers.  A number of explanations for the results include inter-eye transfer from a gene therapy vector, trans-neuronal spread of vector through synaptic transfers mechanisms, mitochondrial migration, brain plasticity, spontaneous recovery, intraocular inflammation and cross contamination between samples.  Regardless, the outstanding questions may require other fresh study designs to tease out the current outcomes provided within their paper, published in the journal, Science Translational Medicine (Volume 12, Issue 573,December 2020).


LHON is a rare progressive disease with an estimated European prevalence of between 1 in 30,000 and 1 in 50,000 patients.  Over >90% of LHON patients carry one of three pathogenic mutations in their mitochondrial DNA (mtDNA) causing a defect in the complex I subunit of the mitochondrial respiratory chain, causing a progressive loss of visual acuity and blindness.  These three prevalent mtDNA point mutations include m.3460G>A (MT-ND1), m.11778G>A (MT-ND4) and m.14484T>C (MT-ND6).  m.11778G>A and are considered the most common mutation worldwide and a target for gene therapy treatment using rAAV2/2-ND4.  One recent approval in the EMA introduced a synthetic analog of co-enzyme Q10, idebenone (Raxone), with an oral medication originally authorized at a daily dose of 900 mg for the treatment of visual impairment in adolescent and adult patients. In the current study, idebenone conducted an open-label, multi-center, retrospective, noncontrolled analysis of visual acuity.   The primary endpoint reported in the EMA EPAR assessment with an estimated difference of logMAR BCVA -0.064±0.061(-0.184, 0.055)[3 letters], p=0.291.  However, the most recent comparable approach is currently focused on the m.11778G>A target, now reported through a series of three studies – RESCUE, REVERSE and REFLECT, distinguished from the duration of study.


As highlighted, results for the gene therapy study presented an allotopic expression strategy which involves the nuclear expression of the wild-type recoded replacement mitochondrial gene (ND4), engineered to carry a “mitochondrial targeting sequence (MTS)”, using mRNA translation and co-translocation of the protein into mitochondria. Commenting on the studythe researchers stated that, “the unexpected observation of a bilateral improvement of visual function prompted us to further investigate the possible transfer of rAAV2/2-ND4 viral vector to the contralateral sham-treated eye by conducting a nonhuman primate (NHP) study equivalent to the human REVERSE study”.  Three NHP animals found a similar study looking at the
equivalent design showing a comparable contralateral eye result.  The authors have postulated several ideas and have concluded that, “the unexpected visual improvement observed in the contralateral noninjected eyes may reflect transfer of viral vector DNA from one eye to the other as demonstrated in our complementary NHP study. However, further investigations are needed to confirm these findings and their underlying mechanisms”.