Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1.
OBJECTIVE
To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use "allotopic expression" by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous.


METHODS
Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened for ND1, ND4, and ND6 mutations in mitochondrial DNA commonly associated with LHON. All patients and maternal relatives also underwent complete neuro-ophthalmic examination, automated visual field testing, pattern electroretinogram (PERG), and OCT3.


RESULTS
Twenty-five subjects with LHON and 21 carriers positive for the G11778A mitochondrial DNA mutation were recruited. Three additional mutations in the ND4 gene, G11719A, G11947A, or G11914A, were detected. Mean retinal nerve fiber layer (RNFL) thickness was 78.3 μm up to 32 months after visual loss. It was 63.5 μm for all affected patients and 100.7 μm for carriers (P < .01). Mean PERG amplitude was lower in affected patients (40% of normal) than in carriers (94% of normal) (P < .01). Four carriers with PERG amplitudes less than 75% of normal had Early Treatment Diabetic Retinopathy Study acuity more than 20/25, mean defect more than -2 dB, and average RNFL thickness more than 80 μm.


CONCLUSIONS
Potential candidates for future gene therapy may include affected patients, as late as 32 months after loss of vision, with mildly reduced RNFL thickness or carriers with low PERG amplitudes and normal RNFL thickness, if the PERG amplitude is a predictor of conversion to LHON in these carriers.
Lam
Byron L
BL
Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Feuer
William J
WJ
Abukhalil
Fawzi
F
Porciatti
Vittorio
V
Hauswirth
William W
WW
Guy
John
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics*; D004596:Electroretinography; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase / Q000235:genetics*; D009412:Nerve Fibers / Q000473:pathology; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D018579:Patient Selection; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000473:pathology; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology
D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase