Bascom Palmer Eye Institute Announces LHON Breakthrough

Research article published in January issue of JAMA Ophthalmology

A research team led by John Guy, M.D., professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine, has pioneered a novel technological treatment for Leber Hereditary Optic Neuropathy (LHON), an inherited genetic defect that causes rapid, permanent, and bilateral loss of central vision in people of all ages, but primarily males ages 20-40. Guy and his team recently advanced their research significantly by demonstrating that the vector, adeno-associated virus or AAV (a small virus that infects humans but is not known to cause disease), coupled with the ND4 gene, was made human grade expressed in the ex vivo human eye and was proven safe in experimental models that are closest to the human eye, suggesting possible progression to a clinical trial.

These latest findings will be shared in the January 23 online edition of the Journal of the American Medical Association Ophthalmology under the title “Safety and Effects of the Vector for the Leber’s Hereditary Optic Neuropathy Gene Therapy Clinical Trial.” Funding for a clinical trial, which would allow injection of therapeutic genes into patients who have visual loss from mitochondrial disease, is currently being sought from governmental and other appropriate sources.

Guy’s preliminary research was funded in 2007 by National Institutes of Health (NIH) and National Eye Institute (NEI) grants totaling $6.1 million. It has been found that mutations in the mitochondria (part of the cell that produces energy) cause LHON. Currently, there is no treatment for this or any other disease caused by mutated mitochondrial DNA. However, Guy and his team previously modified a virus and used it to introduce healthy genes into the mitochondria to correct the genetic defect.

“In research conducted in 2012, we 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,” said Guy. “This research demonstrated that when efficiently introduced into mitochondria, normal DNA can correct a biochemical defect in cellular energy production and restore visual function.”

Mutations in mitochondrial DNA cause a spectrum of neurodegenerative disorders for which usually effective remedies are inadequate. The field of human mitochondrial genetics was born a quarter century ago and the list of neurodegenerative disorders associated with mutated mitochondrial DNA keeps growing. While many different experimental approaches have been proposed, development of a clinically effective therapy has been elusive. “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.”

In Guy’s research, the healthy genes were delivered into the mitochondria via an innovative viral delivery system. Specifically, Guy redirected the AAV to the mitochondria rather than to its typical target, the nucleus, where most genes are housed within the cell. He did so using a mitochondrial-targeting sequence, a peptide chain that directs the transport of a protein. This permitted the replacement of the defective mitochondrial gene with a healthy one, which then restored energy production to the affected ocular cells.

A potential target for therapeutic intervention is to introduce a normal copy of the defective ND4 allele (one of two or more versions of a gene) into retinal ganglion cells, the cell type exclusively affected in LHON. Introducing a normal version of a defective gene has been the basis for more than 1,500 gene therapy clinical trials worldwide, but only one involving a mitochondrial disease (clinical # NCT01267422, conducted in China).

“Other research studies have shown that LHON patients who have lost their vision still have approximately half their retinal cells remaining,” said Guy. “This finding suggests that if you can restore the functioning of those cells through gene therapy, those patients could see again.”

In conjunction with his prior research, Guy explored why only about 50 percent of patients with the genetic mutation develop LHON, while others do not. 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. Regarding his latest research efforts shared in JAMA Ophthalmology, Guy said, “We trust that the discovery of this vector (AAV with the ND4 gene) will serve as an important impetus for an eventual cure for the blinding disease LHON.”

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