Three decades have passed since gene therapy pioneer William W. Hauswirth, Ph.D., and his colleagues at the University of Florida began work on a virus that could safely deliver corrective genes into living animals.
It’s been six years since a multi-university team used gene therapy to give sight to puppies born with a defect that causes blindness.
Now the gene transfer technique is being tested for safety in people in a phase 1 clinical research study conducted by the University of Pennsylvania and the University of Florida with support from the National Eye Institute (NEI) of the National Institutes of Health.
A young adult with a form of hereditary blindness called Leber congenital amaurosis type 2, or LCA2, received an injection of trillions of replacement genes into the retina of one eye this month, making the volunteer one of the first people in the world to undergo the procedure.
In all, six adults and then three children between the ages of 8 and 17 will undergo the gene-transfer procedure at UF over the next year or more before safety data is fully evaluated.
Positive results from animal testing
“This is the first study of its kind to investigate inherited blindness,” said Barry J. Byrne, M.D., Ph.D., a professor of molecular genetics and microbiology and director of UF’s Powell Gene Therapy Center.
Hauswirth and Jacobson — the trial’s principal investigator — were among a multi-centre team of NEI-supported clinicians and scientists that first established proof-of-concept for gene transfer for LCA in rodent models of the disease and in a breed of vision-impaired dogs called Briards. Restoration of visual function in dogs occurred in 2001 and has been described as remarkable and long-lasting.
“The idea of the therapy is simple,” said Hauswirth, UF’s Rybaczki-Bullard professor of ophthalmic molecular genetics. “If cells are missing a gene for a vital function, such as vision, the therapy is to replace that gene.”
After rigorous preclinical safety studies in animals, including demonstrating the safety of the procedure in non-human primates, the investigators began a human clinical trial.
Using evolution to our advantage
In LCA-type diseases, photoreceptor cells are unable to respond to light. NEI and NEI-supported researchers have found that LCA2 is caused by mutations in the RPE65 gene, which produces a protein with the same name that is vital for vision. This trial will evaluate the use of a modified adeno-associated virus — an apparently harmless virus that already exists in most people — to deliver RPE65 to the retina.
“Viruses have evolved a way to get into cells very efficiently, more efficiently than anything else we know, to deliver a piece of genetic material to a cell,” Hauswirth said. “So all we’re doing is using evolution to our advantage — in this case, to deliver our therapeutic gene.”
The actual medical technique used to transfer the gene is not unusual, said Kaushal, who directs the vitreo-retinal service in the UF College of Medicine.
“The procedure involves two incisions that give the surgeon access to the surface of the retina,” Kaushal said. “Then, fluid containing the virus is injected with a syringe and it creates a bubble. The virus will then be taken up by the photoreceptor cells and the retinal pigment epithelial cells and will theoretically produce the protein that these patients are missing.”
LCA2 affects about 2,000 people in the US and is one of several incurable forms of blindness collectively known as retinitis pigmentosa, which in turn affects about 200,000 Americans.
Children with LCA2 experience major visual disability that can lead to total vision loss in adulthood. Although vision loss is severe, the structure of the retina — including its connection to the brain — can remain relatively intact for decades before the photoreceptor cells degenerate. – (EurekAlert!)