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.

Figure 1

Fundus photographs of a patient with acute LHON revealed swelling of the right (a) and left (b) optic nerve heads. The arrow indicates the characteristic peripapillary telangiectasia. Automated visual fields showed central scotomas in the left (c) and right (d) eyes. OCT confirmed and quantitated the swelling of the retinal nerve fiber layer (e). Pattern electroretinograms illustrated a decline in ganglion cell function occurred during the acute stages of LHON and before structural evidence of RGC loss (f).

Figure 2

A schematic diagram illustrates the interaction of Complex I dysfunction, decreased ATP production, increased ROS, and apoptosis that culminate in the optic nerve degeneration of LHON and LHON cellular and animal models. ATP—adenosine triphosphate; ROS—reactive oxygen species.

Figure 3

Electrophoresis of mitochondrial proteins isolated from the mouse brain following Complex I immunoprecipitation and counterstained by Coomassie blue are shown in the second lane. The first lane has the molecular weight standards. The table indicates the identity of bands submitted for mass spectroscopy to be subunits of Complex I. (*)—subunits identified within the same excised band. (nd)—not determined.