NIH-funded researchers' develop new mouse model and show effective gene therapy for eye disease

Bascom Palmer Eye Institute's John Guy

A mouse model has been established for Leber hereditary optic neuropathy (LHON), a vision disorder caused by mutations within genes in the "battery packs" of our cells--the mitochondria. And investigators funded by NIH say they were able to develop a gene therapy that could be used to treat it.

Within the mitochondrion are mitochondrial DNA (mtDNA) which carries the instructions for important metabolic processes required to keep the cell topped up with energy. Mutations in genes found in mtDNA can lead to various diseases; one of these is LHON, which affects around 1 in 30,000 in England.

"[Until now] there was no efficient way to get DNA into mitochondria," said John Guy, who is a professor of ophthalmology and is lead author of this study. Their work has been published in the Proceedings of the National Academy of Sciences.

Early symptoms of the disease include blurred vision and eyesight will eventually deteriorate over time. A loss of retinal ganglion cells is at the crux of the pathology and these cells are crucial for carrying visual signals from the retina to the brain, via the optic nerve.

The most prevalent mutation responsible for LHON is in a mitochondrial gene called ND4. Dr. Guy and his lab have been attempting to develop a gene therapy approach to correct this mutation for 15 years now. But one issue with adopting the widely used viral vector is that despite its efficacy in integrating into nuclear DNA--viruses have a harder time penetrating the mitochondria.

In developing his mouse model, Dr. Guy found a way around this. He fixed a virus with the same mutation in ND4 seen in 70% of LHON patients--adding a protein that mitochondria require from outside the organelle since they cannot produce it on their own.

In the hijacked virus they included a fluorescent tag so they could confirm the future progeny of mice which had the defective gene. The mouse model does what is seen in patients with the same disease: optic nerve atrophy, loss of retinal ganglion cells and a decline in visual response.

The next step was providing a gene therapy to reverse it. The researchers packaged a normal ND4 gene into the same type of virus and injected it directly into the eye--leading to marked visual improvements without any side effects from the virus itself.

- here's the release

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