The eyesight of individuals with a rare hereditary disorder, which leads to considerable vision loss in early childhood, improved dramatically—by 100 times—after they underwent gene therapy targeting the genetic mutation responsible for the condition. Notably, some patients saw a staggering 10,000-fold enhancement in their vision when receiving the highest therapy dosage, as reported by researchers from the Perelman School of Medicine at the University of Pennsylvania, who were co-leaders of this clinical trial published in The Lancet.
“A 10,000-fold improvement equates to a patient being able to perceive their environment under moonlight rather than needing bright lighting indoors before treatment,” explained Artur Cideciyan, PhD, the lead author of the study, who is a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “One participant recounted that they could navigate outside at midnight using only the light from a bonfire for the first time.”
The Phase 1/2 trial comprised 15 participants, including three children. Each individual had Leber congenital amaurosis, stemming from mutations in the GUCY2D gene, which is vital for the production of proteins essential for vision. This particular condition, also known as LCA1, affects fewer than 100,000 individuals globally and can lead to severe vision loss starting in infancy.
All participants experienced significant vision impairment, with their best vision being 20/80 or worse—essentially meaning if a person with normal vision could see an object clearly from 80 feet away, these patients would need to move up to just 20 feet to recognize it. Traditional glasses offer limited assistance to these individuals, as they can fix issues with focusing but do not address medical factors contributing to vision loss, such as genetic retinal diseases like LCA1.
The trial evaluated different dosage levels of the gene therapy known as ATSN-101, based on the AAV5 microorganism, which was injected surgically beneath the retina. Initially, groups of three adults received one of three dosage levels: low, medium, and high. Safety assessments were conducted between each dosage increment before advancing to the next cohort. The second phase of the study exclusively involved administering high dosages to both an adult group of three and a pediatric group of three, again following thorough safety evaluations of the previous cohorts.
Participants began to show improvements quickly, generally within the first month of therapy, and these enhancements lasted for at least a year. Ongoing evaluations of the patients are underway. Among the six individuals who received the highest dosage, three achieved the best possible scores in a mobility assessment that varied with different light conditions. Other evaluations incorporated eye charts and tested sensitivity to dim flashes of light in dark settings.
Of the nine patients who were given the highest dosage, two experienced the incredible 10,000-fold enhancement in vision.
“While we anticipated significant potential for vision improvement in LCA1, we were uncertain how responsive patients’ photoreceptors would be to treatment after years of blindness,” said Cideciyan. “It’s gratifying to witness a successful multi-center trial demonstrating that gene therapy can be extraordinarily effective.”
The primary goal of the study was to assess the safety of the gene therapy and its various dosages. Researchers did encounter some side effects among patients, although most were related to the surgical procedure itself. The most frequent issue was conjunctival hemorrhage, which is the breaking of tiny blood vessels beneath the eye’s clear surface and healed fully. Two patients experienced eye inflammation, which was successfully treated with steroids. There were no serious side effects linked to the investigational drug.
This study follows another successful research effort at Penn, which restored sight in patients with a different type of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was utilized to enhance the vision of many individuals affected by a type of LCA caused by mutations in the CEP290 gene. This study, co-led by Tomas S. Aleman, MD, one of the new paper’s authors and a professor of Ophthalmology, successfully involved children for the first time in gene editing work.
“The success of treatment in our recent clinical trials, along with our past experiences, instills hope for viable treatments for roughly 20 percent of childhood blindness resulting from hereditary retinal degenerations,” Aleman remarked. “Our next steps involve perfecting these treatments and addressing early signs of these conditions once safety has been established. We anticipate that similar methods will yield equally encouraging results for other types of congenital retinal blindness.”
For this experimental medicine to gain approval for clinical use, another trial must be conducted, which will involve randomizing participants to receive the treatment at varying dosages, ensuring that neither the patients nor the researchers know who is receiving which treatment. This approach will help eliminate potential biases in the results.
This study received funding from Atsena Therapeutics, Inc. Two of the authors, Andres K. Lauer, MD, and Mark Pennesi, MD, PhD, serve on the company’s clinical and scientific advisory board.
