Patients with a rare inherited disease affecting their sight have experienced quick, sometimes substantial vision improvements after being involved in a gene therapy trial.
The rare inherited condition can cause people to lose much of their sight early in childhood.
But patients in the trial were reportedly 100 times better off after they received gene therapy to address the genetic mutation causing the condition.
Some patients even experienced a 10,000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.
“That 10,000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” said the study’s lead author, Professor Artur Cideciyan, PhD, a research professor of ophthalmology and co-director of the Centre for Hereditary Retinal Degenerations.
“One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”
Fifteen people participated in the Phase 1/2 trial, including three paediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects fewer than 100,000 people worldwide and is abbreviated as LCA1, causes significant amount of vision loss as early as infancy.
All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80—meaning if a typically-sighted person could see an object clearly at 80 feet (24 metres), these patients would have to move up to at least 20 feet (6m) to see it. Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.
The trial tested different dosage levels of the gene therapy ATSN-101, which was adapted from the AAV5 micro-organism and was surgically injected under the retina. For the first part of the study, cohorts of three adults each received one of the three different dosages: Low, mid, and high. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort. A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a paediatric cohort of three, again after safety reviews of the previous cohorts.
Improvements were noticed quickly, often within the first month after the therapy was applied, and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum-possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.
Of the nine patients who received the maximum dosage, two had the 10,000-fold improvement in vision.
“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Prof Cideciyan. “It is very satisfying to see a successful multi-centre trial that shows gene therapy can be dramatically efficacious.”
Moving forward, approval of this experimental medicine for clinical use requires another trial, where participants are randomised to a treatment dose and both patients and those investigating the trial do not know who gets what. Through that, any possible bias in results could be avoided.
- This study was funded by Atsena Therapeutics, Inc. Two of the paper’s authors, Andres K. Lauer, MD, and Mark Pennesi, MD, PhD, are members of the company’s clinical and scientific advisory board.
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