Clinical Trial Uses Gene Therapy to Target Mutations in Mitochondrial Genes

A multidisciplinary research team of scientists, clinicians and biostatisticians led by John Guy, M.D., professor of ophthalmology and director of the ocular gene therapy laboratory at the Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine, has pioneered a gene therapy approach for Leber Hereditary Optic Neuropathy (LHON), an inherited genetic disorder that causes rapid, permanent, and bilateral loss of vision in people of all ages, but primarily men ages 20-40. Guy’s preclinical research has been funded since 2007 by National Institutes of Health and National Eye Institute (NEI) grants totaling $6.1 million. A similar amount will fund a new five-year clinical trial that started April 1.

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 until now. LHON is caused by genetic defects inside mitochondria, the energy factories inside cells. Through this trial, patients who have visual loss from LHON will receive an injection of a mitochondrial gene into the vitreous of the eye. While there have been approximately 1,800 reported clinical trials using gene therapy, all but one have targeted the nucleus, or the “brain” of the cell, and the home for most of the cell’s DNA. This new trial is among the first to target a disease caused by a defective gene located inside the mitochondria.

“A wide range of other conditions, including aging, cancer, and Parkinson’s disease, are also caused by mutations in the mitochondria,” said Guy. “This novel approach shows the vast potential for genetic-therapy applications, while helping to address a significant cause of blindness.” About half of all patients with LHON have mutations in the mitochondrial gene ND4, and most other patients carry mutations in one of two related mitochondrial genes. The ND4 protein is part of Complex I, an essential protein that works as part of an assembly line for producing energy inside mitochondria.

The approach in the clinical trial for therapeutic intervention is to introduce a normal copy of the defective gene into retinal ganglion cells (RGCs), the cell type exclusively affected in LHON. Replacing 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, located in China). One of the major drawbacks for treating mitochondrial diseases by gene therapy has been a lack of availability of practical methods.

Guy developed an approach to deliver the normal ND4 gene into retinal cells using a virus. But since viruses are designed by nature to infiltrate and take over a cell’s nucleus, the next challenge was how to target the gene into mitochondria. Guy’s solution was to create an ND4 gene that is delivered to the nucleus, but modified so that the ND4 protein carries a mitochondrial address label. In experimental models, they have found that this approach is safe and effective to replace the ND4 gene and that doing so prevents deterioration of the retinal cells that form the optic nerve. This research demonstrates that when efficiently introduced into mitochondria, normal DNA can correct a biochemical defect in cellular energy production and restore visual function.
“Other research studies have shown that LHON patients who have lost their vision still have some sensitivity to light,” said Guy. “This indicates 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 male 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. Guy and his team recently advanced their research significantly by demonstrating that the vector (the adeno-associated virus, AAV, with the ND4 gene) was made human grade and proven safe in experimental models that are closest to the human eye. With the Food and Drug Administration having recently approved the investigational new drug (AAV-ND4 gene, IND#15941), a phase I trial of the approach begins in April and will conclude five years later. The trial is funded through an approximately $6 million cooperative agreement from NEI (EY023558). The research leading up to the trial was funded by another award (EY018600) through NEI’s Translational Research Program on Therapy for Visual Disorders.

Louise Wideroff, Ph.D., a program director in NEI’s Division of Extramural Research, said, “The continuing progress in this research—especially its movement from the lab into human trials — is cause for excitement and optimism, not only for families with LHON but for families affected by other mitochondrial disorders.”

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