Study: 100x improvement in sight detected after gene therapy trial

(Image credit: AdobeStock/Елена Бутусова)

The vision of patients diagnosed with a rare inherited condition that causes them to lose much of their sight early in their childhood was demonstrated to be 100 times better after they received gene therapy to address the genetic mutation causing it.

According to the clinical trial, published in The Lancet, some patients even experienced a 10,000-fold improvement in their vision after receiving the highest dose of the therapy.¹

“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,” the study’s lead author, Artur Cideciyan, PhD, a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations, said in a news release.² “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”

According to the Penn researchers, 15 patients participated in the Phase 1/2 trial, including 3 pediatric patients. The patient was diagnosed with Leber congenital amaurosis which was a result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. Researchers noted the condition, which affects less than 100,000 people globally. It results in a great amount of vision loss as early as during infancy.

Researchers also pointed out that the patients had severe vision loss with their best measure of vision being equal to or worse than 20/80. Eyeglasses offer some limited benefits to these patients because they correct abnormalities in the eye’s ability to focus. They cannot address medical causes of vision loss, such as genetic retinal diseases like LCA1.¹

As part of the study, the clinical trial examined a range of dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina. During the initial part of the study, cohorts of three adults each received 1 of the 3 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 pediatric 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 9 patients who received the maximum dosage, 2 exhibited a 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,” Cideciyan said in the news release. “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”

In the study, the researchers also set out to figure out the safety of the gene therapy and its varying dosage levels. Researchers found that some of the patients did experience side effects, with the most common issue being conjunctival hemorrhage. They noted that 2 patients experienced eye inflammation that was reversed with the administration of a round of steroids. They detected no serious side effects attributed to the study drug.

The research comes in the wake of another ophthalmological trial at Penn restoring sight in patients with a different form of LCA. Earlier this year, Penn researchers used CRISPR-Cas9 gene editing to improve the sight of many patients with a form of LCA tied to mutations in the CEP290 gene.³

That research was co-lead by Tomas S. Aleman, MD, a co-author of the new paper and the Irene Heinz-Given and John LaPorte Research Professor in Ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations. The previous study used similar tests and was the first time children were involved in any gene editing work.³

“The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20 percent of infantile blindness caused by inherited retinal degenerations,” Aleman said in the news release. “The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.”

Going forward, the approval of the experimental medicine for clinical use will require an additional trial, with participants being randomly assigned to a treatment dose and both patients and those investigating the trial not knowing who gets what. By doing that, the potential for bias in results could be avoided.^1,2

“ATSN-101 has the potential to be a first-in-class treatment for LCA1, a blinding condition with no approved treatment,” the researchers concluded in the study. “The favorable safety profile and improvements in retinal sensitivity observed in this phase 1/2 clinical trial are supportive of a future randomized, controlled phase 3 trial to further investigate the efficacy and safety of this novel subretinal gene therapy.”

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.²

References:

1. Yang, Paul et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study. The Lancet, Volume 404, Issue 10456, 962 - 970

2. 100x improvement in sight seen after gene therapy trial. EurekAlert! Published September 5, 2024. Accessed September 11, 2024. https://www.eurekalert.org/news-releases/1056835

3. Pennmedicine.org. Published 2024. https://www.pennmedicine.org/news/news-releases/2024/may/gene-editing-improves-sight-in-children-treated-for-blindness