Their research was published in the prestigious journal Proceedings of the National Academy of Sciences on April 20.
Currently, there is no cure for LHON, but Guy and his team successfully modified a virus and used it to introduce healthy genes into the mitochondria to correct the genetic defect. Using experimental models, they proved that it is both safe and effective to replace mutated genes with healthy ones and that doing so prevents deterioration of the retinal cells that form the optic nerve. The research demonstrates that when efficiently introduced into mitochondria, normal DNA can correct a biochemical defect in cellular energy production and restore visual function.
“A wide range of other factors, including aging, cancer, and Parkinson’s disease, are also caused by mutations in the mitochondria,” said Guy. “This new approach shows the vast potential for genetic-therapy applications, while helping to address a significant cause of blindness.”
The healthy genes were delivered into the mitochondria through an innovative viral delivery system where the adeno-associated virus is redirected from its typical target, the nucleus, to the mitochondria. Using a mitochondrial-targeting sequence (a peptide chain that directs the transport of a protein), the defective mitochondrial gene was replaced with a healthy one, restoring energy production to the affected ocular cells.
“Other research studies have shown that LHON patients who have lost their vision still have some sensitivity to light,” said Guy. “This indicated that if you can restore the functioning of those cells through gene therapy, those patients could see again.” In conjunction with his research, Guy explored why only about 50 percent of patients with the genetic mutation develop LHON.
Known for exploring gene therapy as a potential treatment for diseases of the optic nerve, Guy holds several patents related to mitochondrial gene therapy biotechnology. In his next line of research, he will attempt to incorporate all three genes that cause LHON into a single viral carrier and seek FDA approval to begin human trials.
Other members of the research team from Bascom Palmer included Hong Yu, Ph.D., post-doctoral associate; Rajeshwari D. Koilkonda, Ph.D., assistant scientist in ophthalmology; Tsung-Han Chou, Ph.D., post-doctoral associate; Vittorio Porciatti, D.Sc., research professor of ophthalmology; and Sacide S. Ozdemir, Ph.D., post-doctoral fellow.
Two National Institutes of Health/National Eye Institute grants totaling $6.1 million funded the research, which began in 2007.
University of Miami