Vision Improvements Reported in Choroideremia Gene Therapy Clinical Trial

January 16, 2014

Initial results are in from the first six patients in the groundbreaking choroideremia gene therapy clinical trial conducted by Oxford University researchers in the United Kingdom, and the study’s surgeon and lead investigator, Robert MacLaren, M.D., is very pleased.

“I went outside this evening and for the first time in a long time I could see the stars in the sky. This is such an amazing thing, I hope it lasts forever,” said Wayne Thompson, a 43-year-old in the study’s second group of six participants.

“His comment is far more impressive than all the tests we do,” says Dr. MacLaren.

Results for the Phase I/II study, which began in late 2011, were published in The Lancet. Demonstrating safety is the primary goal of the trial, and the emerging treatment has been safe thus far. In addition, five of six participants in the initial study group have sustained vision improvements in their treated eyes in dim settings.

The two patients who entered the trial with the worst visual acuity showed significant improvements in reading an eye chart. One went from 20/300 to 20/120 after treatment. The other improved from 20/80 to 20/40. Both patients had lost their foveas to advanced retinal degeneration. The fovea is a tiny pit in the center of the retina that’s rich in cones, the cells that provide central and color vision and the ability to perceive details and see in bright settings.

“We are delighted by the results reported by Dr. MacLaren,” says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “This is not only great news for people with choroideremia, it is a big step forward for the entire retinal gene therapy field.”

While the vision improvements have been heartening for Dr. MacLaren, he is also pleased that the subretinal injections of the treatment, which cause a temporary retinal detachment, have not been detrimental.

“My main goal was to detach the fovea, get the treatment in and get the vision back to baseline. I didn’t expect the foveas to degenerate, and I wouldn’t have done the study if I had,” says Dr. MacLaren. “But some patients have many years of useful vision left. I would have felt personally responsible if things hadn’t gone as planned.”

He credits the use of a foot pump for giving him more control of the injection and reducing the risk of irreparable damage. “The pump provides slow, sustained injection of fluid,” he explains. “I would not claim that detaching the fovea is completely without complications; there will be because the surgery is complex. What I am saying, though, is that the principle of detaching the fovea to inject a therapeutic dose of virus under it is sound.”

The injected fluid contained healthy copies of the CHM gene which were inserted into a human-engineered adeno-associated virus, or AAV. The virus is designed to penetrate retinal cells to deliver the therapeutic genetic cargo.

Twelve people will be treated in the Phase I/II trial. Two dose levels are being evaluated. The study is ongoing for higher-dose patients. Dr. MacLaren and his colleagues are planning the Phase IIb study, which will enroll 30 patients. He also hopes to treat the second eyes of patients from the Phase I/II.

Other human studies of choroideremia gene therapy are planned. The Alberta Ocular Gene Therapy Team, at the University of Alberta in Edmonton, is scheduled to launch a Phase I human study in the first half of 2014. The 12-person trial will be the first-ever in Canada for an inherited retinal-disease gene therapy.

“We have helped Dr. Ian MacDonald from the Alberta team by providing him with our human data for his regulatory submission,” says Dr. MacLaren. “We have also had conversations with other gene therapy specialists in the U.S. who are interested in choroideremia. We have been open and collaborative, and we hope to help them get regulatory approval for further clinical trials.”

Jean Bennett, M.D., Ph.D., at The Children’s Hospital of Philadelphia, is planning to launch a choroideremia gene therapy clinical trial in 2014. "Dr. MacLaren’s paper is very exciting as it marks a major milestone in developing a treatment for choroideremia. The early results from this small group of patients are encouraging from both safety and efficacy standpoints,” she says.

The U.K. clinical trial is funded by a partnership between the Wellcome Trust and the U.K. Department of Health. The Foundation Fighting Blindness provided funding over two decades for lab studies that helped make choroideremia gene therapy clinical trials possible. Much of that support went to Miguel Seabra, Ph.D., who played a lead role in advancing choroideremia research.

“My lab has been supported by the FFB since 1993 to work on choroideremia — first in the U.S., then in the U.K. The road was long and difficult, but in the end, we reached the objective: provide a possible cure for the disease,” says Dr. Seabra. “Over almost 20 years, we progressed to gain an understanding of the molecular basis of choroideremia, generate mouse models of the condition through genetic engineering and develop genetic therapy approaches.”

Choroideremia affects approximately 1 in 50,000 people, or about 6,000 people in the United States. Mutations in the CHM gene lead to degeneration of the choroid — the vasculature that provides oxygen and nourishment to the retina. Photoreceptors, the cells that make vision possible, and a layer of supportive cells known as the retinal pigment epithelium, are also affected in people with the condition.