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Leber hereditary optic neuropathy: safety and effects of the vector for the gene therapy clinical trial

Researchers have developed a novel strategy for treatment of Leber hereditary optic neuropathy ( LHON ) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV ( ND4 ) mitochondrial gene.

A study has demonstrated the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial.

In a series of laboratory experiments, researchers have modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence ( allotopic expression ). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis.

During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography.
Researchers tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON.

Investigators found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I.
In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve.

Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells.

Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions.

In conclusion, expression of the allotopic ND4 vector in the ex vivo human eye, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitochondrial DNA in the patients. ( Xagena )

Koilkonda RD et al, JAMA Ophthalmol 2014; Epub ahead of print