A new treatment for patients with a form of congenital retinal blindness has shown success in improving vision, according to new results.
What is Leber Congenital Amaurosis?
Leber congenital amaurosis (LCA) is an inherited retinal degenerative disease characterized by severe loss of vision at birth.
A variety of other eye-related abnormalities including roving eye movements, deep-set eyes, and sensitivity to bright light also occur with this disease. Some patients with LCA also experience central nervous system abnormalities.
The treatment was designed for patients with CEP290 mutations and a diagnosis of Leber congenital amaurosis (LCA). CEP290 acts as a gate between two compartments of photoreceptor cells a type of sensory neuron in the retina that converts light into signals that provide vision.
Primary photoreceptor blindnesses — such as those caused by CEP290 mutations are the most common form of LCA and they are currently not treatable.
In this clinical study at sites in the United States and Europe, participants received an intraocular injection of an oligonucleotide a short RNA molecule created to reduce the mutant CEP290 protein levels in the photoreceptors and restore retinal function.
“It was very dramatic to see one of the patients improve from only being able to differentiate light or dark to reading many letters on an eye chart at two months following the first injection,”
said lead author Artur V. Cideciyan, PhD, a research professor of Ophthalmology.
“So, we performed a thorough interim analysis of all results from all patients.”
Ten patients received at least one injection into their worst-seeing eye. At three months after the first injection, half of the patients showed improvements in visual acuity, measured by the ability to either read letters, or distinguish direction of black and white bars.
The most basic functions of photoreceptors are to receive and then signal light.
This aspect of vision was tested in patients by presenting flashes of light in the dark and measuring the dimmest flash intensity detected.
Treated eyes could detect on average more than six-fold dimmer lights three months after the injections compared to before.
The results were highly statistically significant. Evaluations with two colors of flashes suggested that it was the cone photoreceptors used for daytime vision that were improving with the treatment.
“This therapy to repair the genetic defect in LCA10 is a breakthrough in treatment strategy and will open the door for clinical trials in other patients with this condition and other similar conditions that are currently untreatable,”
said Samuel G. Jacobson, MD, PhD, a professor of ophthalmology and co-lead author of the study.
All patients enrolled so far into the study had two different CEP290 mutations. The p.Cys998X mutation causing a splicing defect was common in all patients and was specifically targeted by the oligonucleotide.
“We performed an extreme form of personalized medicine where we targeted not just a specific gene but a specific mutation in a gene,”
“It is gratifying to see clinical evidence supporting the action of this oligo predicted from basic science. In the future, we hope to evaluate patients carrying two identical splicing mutations to determine whether the efficacy of the injection might be even greater.”
The authors note that the clinical trial is ongoing to measure safety and efficacy of the injections long-term and the effects of further doses.
Surprisingly simple measures can improve the lives of young people with retinal dystrophies. And some treatments are looking good in early trials.
To the dismay of both patients and physicians, ophthalmology currently offers no cures or therapies for inherited retinal dystrophies.
These disorders result in progressive, sometimes blinding, vision loss during childhood.
However, the science of diagnosing, genotyping and managing this broad and sometimes misunderstood group of diseases is rapidly advancing and, in the process, improving lives:
Children with retinal dystrophies can benefit from a definitive diagnosis and attentive follow-up, which may include corrective lenses, low vision aids and treatment of accompanying genetic conditions.
Identification of gene mutations as well as the availability of genetic testing has proven beneficial for patients and their families by allowing them to adjust to a future that includes visual disability.
More hearteningly, research is now substantial enough that effective therapies may not be such a distant dream:
Human trials that treat a mutation in the RPE65 gene, which causes some cases of Leber congenital amaurosis, have produced promising results.
Two drugs, fenretinide and isotretinoin, have shown promise in early animal studies for treating Stargardt macular dystrophy. Although they are not being pursued aggressively by the drug makers, isotretinoin was shown to suppress the buildup of the toxic pigment lipofuscin, which leads to loss of vision in Stargardt disease. Likewise, fenretinide interferes with the production and accumulation of the toxin A2E that leads to lipofuscin deposits.
Clinical trials of fenretinide are in place for treating age-related macular degeneration, though none are planned for Stargardt.
“It could possibly work in Stargardt disease, but we may never find out until we have clinical trials,”
said Peter J. Francis, MD, PhD, associate professor of retinal and ophthalmic genetics at the Casey Eye Institute, Oregon Health & Science University in Portland. Dr. Francis noted as well that clinical trials of isotretinoin have not been initiated for Stargardt disease, and one possible reason is concern over the drug’s side effect profile.
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