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B. L. Lam, W. J. Feuer, V. Porciatti, F. Abukhalil, A. Morante, J. R. Guy; Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial: Preparatory Phase Year One. Invest. Ophthalmol. Vis. Sci. 2010;51(13):994.
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To report the first-year patient profiles of the preparatory phase of the LHON Gene Therapy Clinical Trial. This Study aims to identify and characterize affected patients and carriers with mtDNA G11778A mutation for planned gene therapy that will utilize "allotopic expression" by delivering copies of normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells (RGC) via an adeno-associated virus vector injected into the vitreous. The cytoplasmically synthesized ND4 protein is directed to the mitochondria by appending an N-terminus mitochondrial targeting sequence.
Male and female LHON patients with acute or chronic visual loss in one or both eyes as well as their asymptomatic maternally-related family members were screened for ND1, ND4 and ND6 mtDNA mutations commonly associated with LHON. All patients and maternal relatives underwent complete neuro-ophthalmic examinations, automated visual fields, pattern electroretinogram (PERG), and OCT every 6 months.
From December 2008 to November 2009, 46 subjects with LHON G11778A (25 affected (17 males), mean age 31.8 years (range 9.9-61.5); 21 carriers (18 females), mean age 43.2 (9.3-84.7) years) were recruited. Median time from visual loss was 35 months. Genetic analysis was positive for mtDNA G11778A homoplasmy in all subjects. Also noted were two additional mutations in the ND4 gene, G11719A changing the amino acid Gly to Glu at amino acid 320 (7 subjects) and A11947G resulting in no amino acid substitution (3 subjects). There were no mutations in ND1 or ND6. Two affected patients had optic disc edema, the rest optic atrophy. Mean Cirrus SD-OCT mean RNFL thickness was 66.0 µm for affected and 91.4 µm for carriers (p<0.01). Mean PERG amplitude was 0.46 µV for affected versus 0.98 µV for carriers (p<0.01). Four carriers had PERG amplitude reduced to less than 75% normal. Mean PERG phase was higher in the affected compared to carriers (p<0.001).
RGC survival with dysfunction many months after visual loss may provide a long window of opportunity for intervention and rescue by AAV mediated ocular gene delivery of a normal ND4 subunit. It would also correct for secondary mutations with expression of the normal ND4 protein. Based on these results, possible candidates for future gene therapy may include affected patients with mildly reduced RNFL or carriers with low PERG amplitudes and normal RNFL if the PERG is a predictor of conversion to LHON in these carriers. Reduced PERG amplitude but increased phase occurred in affected suggests a more preferential impairment of the parvocellular visual pathway in LHON.
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