Research is finding key patient benefits to gene therapy as a promising treatment strategy for Leber's hereditary optic neuropathy (LHON).
This article was reviewed by Patrick Yu-Wai-Man, FRCOphth, FRCPath, BMedSci, MBBS, PhD
Data from two clinical studies of Leber’s hereditary optic neuropathy (LHON) showed substantial visual improvements in patients with both disease durations of less than six months and between six months and one year. The improvements resulted from a unilateral injection of a gene therapy vector (GS010) and remarkably, the viral vector seemed to be carried over to the untreated eye.
The mechanism of action for these unexpected results need to be clarified with further experimental work.
LHON is the most common cause of mitochondrial blindness with a minimal prevalence of one in 30,000 individuals in the population. It causes blindness mostly in young adult men with a peak age of onset in the third decade of life. It is invariably a bilateral disorder in which the fellow eye becomes affected within three to six months after disease onset in the first eye.
Both eyes are affected simultaneously in about 25% of patients, according to Patrick Yu-Wai-Man, FRCOphth, FRCPath, BMedSci, MBBS, PhD, an academic neuro-ophthalmologist with faculty positions at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, in the UK.
Three primary mutations within the mitochondrial genome cause about 90% of cases worldwide, namely, m.3460G>A, m.11778G>A and m.14484T>C, with m.11778G>A being the most common mutation by far, accounting for over 70% of those affected with LHON. Unfortunately, most affected patients remain legally blind with vision worse than 1.3 logarithm of the minimum angle of resolution (logMAR) or 3/60 in Snellen equivalent.
Given the poor prognosis, there is an urgent clinical need to identify effective treatments for this blinding optic nerve disease.
“Gene therapy is obviously a very attractive treatment option, because the underlying pathophysiology is due to insufficient amount of the wild-type protein,” Dr. Yu-Wai-Man said. “Therefore, if the defective gene is replaced, we should be able to rescue the retinal ganglion cells, preserving function and improving the visual prognosis.”
He described the principles of allotopic gene expression that involves inserting the mitochondrial gene of interest, in this case MTND4, into the nuclear genome with a modified viral vector. The wild-type protein produced has a specific mitochondrial targeting sequence that directs it to be imported into the mitochondrial compartment.
The use of an intravitreal injection is a big advantage for this treatment approach as it is a relatively straightforward procedure that provides direct access to the inner retina. Previous preclinical work indicates that allotopic expression is able to rescue the retinal ganglion cells from the deleterious effects of the m.11778G>A mutation.