The results, published online in the New England Journal of Medicine, focus on a subset of trial participants who routinely underwent extensive tests of their vision and imaging of the retina from baseline up to six years after treatment. These in-depth examinations revealed that the areas of treated retina rapidly gained visual sensitivity, expanded and then contracted.
“Gene therapy for LCA demonstrated we could improve vision in previously untreatable and incurable retinal conditions,” said Samuel G. Jacobson, MD, PhD, who led the clinical trial at the University of Pennsylvania’s Scheie Eye Institute, Philadelphia. “Even though the current version of the therapy doesn’t appear to be the permanent treatment we were hoping for, the gain in knowledge about the time course of efficacy is an opportunity to improve the therapy so that the restored vision can be sustained for longer durations in patients.”
The results, announced at the 2015 Association for Research in Vision and Ophthalmology annual meeting, contribute to the bigger picture of the potential benefits—and remaining problems to solve—in the field of gene therapy for LCA and other diseases that affect the retina.
About 10 percent of people with LCA carry a mutated form of the gene RPE65, which makes a key protein found in the retinal pigment epithelium, a layer of cells that nourish the light sensors or photoreceptor cells of the retina. The RPE65 protein is critical for vision. In the retina, millions of photoreceptors detect light and convert it into electrical signals that are ultimately sent to the brain. Photoreceptors rely on the RPE65-driven visual cycle to recharge their light sensitivity. They also need RPE65 for their long-term survival. In LCA, the cells eventually die, muting eye-to-brain communication.
Dr. Jacobson, along with Artur V. Cideciyan, PhD, University of Pennsylvania, and William W. Hauswirth, PhD, University of Florida, Gainesville, began the trial in 2007. Fifteen people with LCA received retinal injections of a harmless virus engineered to carry healthy RPE65 genes. This gene therapy relies on viral vectors as a means to deliver instructions for making the desired protein. In this case, the virus was designed to produce healthy RPE65. Dr. Hauswirth led the group that designed and produced the virus-gene material for testing in patients.
“Within days of the injections, some patients reported increases in their ability to see dim lights they had never seen before. It was remarkable for us to get this feedback that things were indeed changing positively,” said Dr. Jacobson.
In addition to the rapid onset of greater light sensitivity, the researchers discovered changes to another component of vision that occurred slowly. Four of the 15 patients started relying on an area of the retina near the gene therapy injection site for seeing letters. Normally, the fovea with its high density of photoreceptors is responsible for seeing fine details.
“For some patients, preferential use of the treated area for seeing letters came about spontaneously about a year after the gene therapy and remained functional for up to six years,” said Dr. Cideciyan, who reported these findings in Investigative Ophthalmology & Visual Science in January.
For the current study, Dr. Jacobson’s team also examined the relationship between structure and function in the retina. Importantly, these results showed that photoreceptors continued to die at the same rate as they do in the natural course of the disease, regardless of treatment. The researchers concluded that gene therapy with RPE65 boosted the visual cycle, but did not delay photoreceptor cell death. Hence, the short-term gains in visual function.
“We now have six years of data showing that a gene therapy approach is safe and that it successfully improves vision in people with this blinding disease,” said Paul A. Sieving, MD, PhD, director of NEI. “As with any application of a novel therapy, it now needs to be fine-tuned. More research is needed to understand the underlying biology and how we can preserve or restore photoreceptors for a lifetime. Restoring vision is at the heart of the NEI’s Audacious Goals Initiative, an effort to strategically fund research aimed at developing the knowledge and technology to make this goal a reality.”
Dr. Jacobson’s latest results are consistent with another independent investigation performed at Moorfields Eye Hospital and University College London. Those investigators found that retinal sensitivity improved in their LCA patients treated with gene therapy, but then it diminished after 12 months.
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Patients with AIDS at Increased Risk for AMD
Patients with acquired immunodeficiency syndrome have a fourfold increase in their risk of developing intermediate-stage age-related macular degeneration compared to people of the same age who are not infected with HIV, according to results from the Longitudinal Study of the Ocular Complications of AIDS (LSOCA). The results of the study, led by the National Eye Institute-funded Studies of the Ocular Complications of AIDS Research Group, were published online in the American Journal of Ophthalmology.
“With HIV and AIDS patients living longer than ever before, they are at an increased risk of developing several age-related diseases at an earlier age than HIV-uninfected people including cardiovascular disease and diabetes,” said Douglas A. Jabs, MD, MBA, professor of ophthalmology and medicine at the Icahn School of Medicine at Mount Sinai, and the lead author of the new study. “Their increased risk for age-related diseases in general led us to analyze how these patients are impacted by one of the most common age-related eye diseases, macular degeneration.”
To determine how AIDS may contribute to AMD, Dr. Jabs and colleagues enrolled 1,825 patients ages 13 to 73 years with AIDS at 19 sites in United States between 1998 and 2011. The investigators graded retinal photographs for AMD and compared participants in the LSOCA cohort to published data on an HIV-uninfected, age-matched population from the Beaver Dam Offspring Study, which also graded retinal photographs for AMD features. The results showed that the prevalence of intermediate-stage AMD in patients with AIDS was nearly 10 percent and, when adjusted for any age differences, was approximately fourfold greater than that in the Beaver Dam Study.
The researchers also determined that the increased prevalence of AMD in the LSOCA cohort was not related to any drug or class of drugs used to treat HIV infection. Rather they point out that antiretroviral-treated, immune-restored, HIV-infected patients do not have normal immune systems; instead and on average they have immunologic changes similar to those seen in patients who are not infected who are older than 70 years of age, a phenomenon termed “immunosenescence.”
“Although the underlying mechanism leading to this increase in AMD in persons with AIDS is not yet known, it may relate to the state of chronic immune activation and systemic inflammation seen in these patients,” said Dr. Jabs. Dr. Jabs and colleagues note that further exploration of these findings may provide the opportunity to better understand the roles of immunosenescence and systemic inflammation in the development of AMD, which in turn could lead to new treatments. The results also add to the growing body of research suggesting that antiretroviral therapy-treated, immunorestored, HIV-infected persons may experience accelerated and accentuated aging.
Ebola Virus Persists in the Eye
Live Ebola virus can persist within the eyes for months after a patient recovers from acute Ebola viral disease (EVD), according to a case report published in the New England Journal of Medicine and presented at the ARVO 2015 annual meeting.
Despite the presence of Ebola virus within one patient’s eye, samples from his tears and conjunctiva tested negative for virus, indicating that casual contact with Ebola survivors carries no risk. The finding points to a need for infection control precautions when Ebola virus disease survivors undergo invasive procedures involving the eyes. It also highlights the need for follow-up care for patients who have recovered from Ebola virus disease.
The case report describes a 43-year-old physician who was working in an Ebola treatment unit in Sierra Leone who became infected with Ebola virus. He was transported to the United States and treated at Emory University Hospital’s Serious Communicable Disease Unit for 40 days, including 12 days of mechanical ventilation and 24 days of renal replacement therapy.
Two months after his discharge from the hospital, the patient was evaluated at the Emory Eye Center following the development of acute anterior uveitis and severe hypertension in one eye.
“The current outbreak has resulted in the largest number of EVD survivors in history. EVD survivors require ongoing medical care to manage complications from the infection that may develop during recovery,” says Jay Varkey, MD, assistant professor of medicine in Emory University School of Medicine.
“Following recovery from Ebola virus disease, patients should be followed for the development of eye symptoms including pain, redness, light sensitivity and blurred vision, which may be signs of uveitis,” says Steven Yeh, MD, associate professor of ophthalmology at Emory.
The patient was treated with topical corticosteroids and medications to decrease the elevated pressure within the eye. Removal of fluid by an anterior chamber paracentesis demonstrated live Ebola virus.
“To safely evaluate and treat EVD survivors who develop complications in the eye and other immune-privileged sites of the body, health-care providers who perform invasive procedures should develop standard operating protocols for: safely donning and doffing personal protective equipment; handling laboratory specimens; and managing medical waste,” said Dr. Varkey.
The patient has experienced visual recovery following therapy for the uveitis and has ongoing ophthalmic follow-up. These findings have implications for the thousands of Ebola virus disease survivors in West Africa and also for health-care providers who have been evacuated to their home countries for ongoing care. Surveillance for the development of eye disease in the post-Ebola period is needed. REVIEW
