New Research: Gene Therapy Restores Some Vision in Clinical Trials for Leber Congenital Amaurosis (LCA)

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Gene therapy for the treatment of specific eye and retinal disorders, such as Leber congenital amaurosis (LCA), has shown promise, but research has produced uneven results thus far and has not produced a cure.

To date, gene therapy studies have raised concerns among researchers, including inconsistent initial and longer-term results, such as this LCA gene therapy study from the National Eye Institute, which reported that cells in the eye crucial for vision [i.e., photoreceptors] continued to diminish in number, despite improved eyesight that resulted from the treatment.

This month, however, at the 2015 Annual Meeting of the American Academy of Ophthalmology, Albert M. Maguire, MD presented positive results from a Phase 3 clinical trial of a gene therapy treatment for Leber congenital amaurosis (LCA) that produced “substantial restoration of vision in patients who were progressing toward complete blindness.” Dr. Maguire is Professor of Ophthalmology at the Scheie Eye Institute of the University of Pennsylvania and a researcher at the Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia (CHOP).

Dr. Maguire presented his findings after the October 5, 2015 announcement of positive clinical trial results by Spark Therapeutics, Inc. On the basis of these trial results, Spark plans to submit their gene therapy treatment, called SPK-RPE65, to the United States Food and Drug Administration for potential approval in 2016.

About Leber Congenital Amaurosis (LCA)

LCA is caused by mutations in a gene involved in vitamin A metabolism called RPE65. The disease negatively affects a person’s eyesight in two ways:

  • First, the inability to process vitamin A reduces the ability of specialized nerve cells in the retina, called photoreceptors, to send visual information to the brain. The retina is the layer of tissue that lines the inside surface of the eye.
  • Second, the disease causes early death of some photoreceptor cells. As a result of these two disease mechanisms, people with LCA are born with limited vision that diminishes over many years as photoreceptor cells are progressively lost.

Here is another definition, excerpted from the Foundation Fighting Blindness, a longtime supporter of gene therapy treatments and a sponsor of the clinical trial:

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.

a retina with Leber's congenital amaurosis
A retina with LCA

Individuals with LCA have very reduced vision at birth. Within an infant’s first few months of life, parents usually notice a lack of visual responsiveness and unusual roving eye movements, known as nystagmus.

Eye examinations of infants with LCA reveal normal appearing retinas. However, electroretinography (ERG) tests, which measure visual function, detect little if any activity in the retina. A low level of retinal activity, measured by ERG, indicates very little visual function. ERG tests are key to establishing a diagnosis of LCA.

Although the appearance of the retina undergoes marked changes with age, vision usually remains fairly stable through young adult life. Long term visual prognosis remains to be defined. Visual acuity in patients with LCA is usually limited to the level of counting fingers or detecting hand motions or bright lights. Some patients are also extremely sensitive to light (photophobia). Patients with remaining vision are often extremely farsighted.

LCA is most typically passed through families by the autosomal recessive pattern of inheritance. In this type of inheritance, both parents, called carriers, have one gene for the disease paired with one normal gene. Each of their children has a 25 percent chance (or 1 chance in 4) of inheriting the two LCA genes (one from each parent) needed to cause the disorder. Carriers are unaffected because they have only one copy of the gene. At this time, it is impossible to determine who is a carrier for LCA until after the birth of an affected child.

About Spark Therapeutics, Inc.

Spark Therapeutics is a developer of gene therapy products for the treatment of debilitating diseases, including inherited retinal dystrophies, such as LCA. Spark’s lead gene therapy candidate is for the treatment of RPE65-related blindness.

Spark was spun out of The Children’s Hospital of Philadelphia (CHOP) in October 2013, along with a $50 million capital commitment. In October 2014, Spark opened their new headquarters at the University City Science Center in West Philadelphia. Spark is building on the work of CHOP’s Center for Cellular and Molecular Therapeutics (CCMT), established in 2004 as a center for gene therapy translational research and manufacturing.

In addition to the Phase 3 program in RPE65-related blindness, the company has a Phase 1/2 program in hemophilia B and preclinical programs to address neurodegenerative diseases and other inherited retinal dystrophies and blood disorders.

More about the Gene Therapy Research for LCA

Excerpted from Gene Therapy Restores Some Vision in Congenital Amaurosis, via Medscape Multispecialty (registration required):

The [Phase 3] study included 31 children (mean age, 15 years) who had visual impairment resulting from Leber’s congenital amaurosis. At baseline, the study population had visual acuity of 20/60 or less and/or visual field constriction beyond 20°. Patients were randomly assigned 2:1, by age and by baseline performance status, to the intervention or to a control group. Groups were well balanced “for a trial this size,” Dr. Maguire reported.

In the active treatment group, patients received single doses of [Spark’s] gene therapy treatment SPK-REP65, containing the normal RPE65 gene, in both eyes via sub-retinal injection. The control group [i.e., study participants who did not receive the gene therapy injection] also received the intervention on a delayed schedule, crossing over to the treatment group at 1 year.

The primary endpoint was functional vision measured by a mobility test administered 1 year after treatment and performed under different environmental light conditions. “This was developed to measure a clinically meaningful outcome; namely, ambulatory vision at light levels encountered during normal activities of daily living,” Dr. Maguire explained.

The Mobility Test

The mobility test was standardized and validated. Twelve templates were used interchangeably to avoid a learning effect, and each navigation course was standardized to contain the same number of turns, obstacles, and obstacle types. Subjects were videotaped performing the test at seven different light levels, and the results were graded by independent readers, who scored the videos for number of errors and time required to complete the navigation course.

The bilateral mobility test scores were notably improved 1 year after gene therapy treatment. “The treatment group showed a prompt, sustained response, while the control group showed no significant change,” Dr. Maguire reported.

Videotapes of the patients before and after treatment graphically demonstrated the effect of the gene therapy on the ability to move about at low light levels, analogous to a parking lot at night. “Pretreatment, patients made numerous errors and could not complete the course in the allotted time. After treatment, they quickly completed the run, with minimum errors,” explained Dr. Maguire. “The treatment subjects demonstrated the maximum improvement that we measure,” said Dr. Maguire.

Visual Acuity Results

An effect on visual acuity was also seen in the treatment group. “A trend toward better visual acuity was, in fact, seen, but it did not reach statistical significance,” Dr. Maguire said. Of note, seven patients had a 15-letter improvement in the first injected eye, and four had a 15-letter improvement in the second treated eye. None of the control subjects experienced these improvements.

Just as important, Dr. Maguire reported, was that there was no decline in mean visual acuity in the treatment group after injection. In addition, there were no serious adverse events related to study drug or the injection procedure.

More Information about the Prior Clinical Trials

You can read more information about all three clinical trials at

Additional Information