Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

Abstract

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial

“…The remaining patients have the G3460A mutation, which affects the ND1 gene (NCBI Entrez Gene 4535), or the T14484C mutation, which affects the ND6 gene (NCBI Entrez Gene 4541). 2 These 3 mutations are considered the primary causes of LHON, and each presents a significant risk for severe visual loss. 3 All are associated with focal degeneration of retinal ganglion cells (RGCs).…”

Leber hereditary optic neuropathy and multiple sclerosis: the mitochondrial connection

“…16,17 Further insights into the molecular mechanisms of MS and LHON will be critical in the development of novel neuroprotective and neuroregenerative therapeutic approaches with the ultimate hope of one day curing these debilitating diseases. 18 Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. We present a case of transient corneal edema after cataract surgery, confined to the LASIK flap.…”

Individual Biomarkers Using Molecular Personalized Medicine Approaches

“…Identification of RPE56 determines the diagnosis. Moreover, animal experiments introducing the normal gene sequence into retinal ganglion cells and clinical trials provided convincing evidence of an effective gene therapy [51] . Furthermore, for cases of pediatric retinal degeneration with an RPE65 gene mutation, a genomics-based gene therapy has been developed.…”