Progress in Development of New Gene Therapy for LCA and Cone-Rod Dystrophy
November, 28, 2011 - Foundation-funded researchers from the University of Florida have taken a major step forward in the development of a vision-restoring, gene-replacement therapy for people with Leber congenital amaurosis (LCA) caused by mutations in the gene GUCY2D. They demonstrated that efficacy of the treatment in a mouse model of the condition was sustained for a year, a significant improvement over earlier studies in which the treatment’s effect lasted three months. The investigators believe that given these latest results, a similar treatment could last for several years or possibly a lifetime in humans.
The research team says that the gene therapy might also be used in treating recessive and dominant forms of cone-rod dystrophy (CORD) caused by mutations in GUCY2D.
The GUCY2D gene therapy effort is one of six new Foundation-funded gene therapy projects that are targeted to move into clinical trials within three years. Investigators on the project include Drs. Shannon Boye and William Hauswirth from the University of Florida and Drs. Samuel Jacobson and Artur Cideciyan from the University of Pennsylvania. The team is receiving $1.5 million from the Foundation to ready the treatment for a human study.
Dr. Boye, lead investigator for the study, says that modifications to the adeno-associated virus (AAV) — the manmade virus used to deliver healthy copies of the gene to photoreceptors — led to a more robust therapeutic effect than achieved previously. Specifically, the capsid, the outer shell of the AAV, was altered to better penetrate photoreceptors. Investigators also ensured that the AAV’s promoter, which controls the potency and localization of the healthy gene’s protein within the photoreceptors, was functioning effectively.
“We are very excited by our overall momentum in gene therapy development,” says Dr. Stephen Rose, chief research officer of the Foundation Fighting Blindness. “Not only do we have more and more efforts moving toward the clinic, but investigators like Dr. Boye are making valuable technical refinements to the treatments, greatly increasing our chances for success and saving and restoring vision.”
Moving forward, Dr. Boye and her colleagues will evaluate the treatment in additional small and large animal models to further confirm the treatment’s safety and efficacy. Additional aims of the three-year project include: screening patients with LCA (GUCY2D) to develop an optimal clinical trial design; producing a gene therapy that is of appropriate quality for use in humans; and collecting data from the preclinical studies to assemble an Investigative New Drug (IND) application for submission to the FDA to begin a clinical trial.
Dr. Boye notes that the treatment, with little or no modification, might also work for people with the autosomal recessive form of cone-rod dystrophy (arCORD) caused by mutations in the GUCY2D.
Additionally, she hopes to use the treatment as the replacement component in a gene therapy for the autosomal dominant form of CORD (adCORD). A gene therapy for adCORD would also need a second component to “knock down,” or silence, the defective GUCY2D gene. In recessive diseases — like LCA and arCORD — the defective gene is already silent, so the “knock down” step is not needed.
Results of the University of Florida LCA (GUCY2D) study were published in the September 2011 issue of the journal Investigative Ophthalmology & Visual Science. |
