Promising Results Reported in Early-Phase Gene Therapy Trials for Two Types of Inherited Blindness

It’s been seven years since the FDA approved the first gene therapy to treat an inherited disorder. Luxturna (voretigene neparvovec) was developed by scientists from the University of Pennsylvania and Children’s Hospital of Philadelphia and is still the only gene therapy approved for hereditary blindness despite considerable attention paid to a range of related conditions.

Now, other researchers from the same Center for Hereditary Retinal Degenerations at Penn’s Perelman School of Medicine reported positive results from a Phase I/II trial of a gene therapy for another of these diseases. At the same time, scientists at the Karolinska Institutet in Sweden reported encouraging results from their gene therapy trial for a different condition causing hereditary blindness.

Both conditions are rare, begin in childhood, and have no current treatments — glasses don’t help. Both open-label trials (participants knew they were receiving the gene therapy) were primarily for safety and dosing. But efficacy end points found significant improvement, mainly in night vision.

Penn trial for patients with Leber congenital amaurosis 1 (LCA1)

LCA1, which is caused by mutations in the GUCY2D gene, affects an estimated 100,000 people globally, causing them to lose much of their sight in early childhood. It is one of more than 20 variants of Leber congenital amaurosis — Luxturna treats another — all of which cause either early onset or congenital blindness. They typically are diseases of dysfunction as opposed to degeneration, which accounts for most congenital retinal diseases.

So rather than seeking to slow progression, which is hard to measure, the Penn researchers wanted to see if they could “turn on” the affected cells, which might restore vision quickly. But most participants in their trial had blindness in one eye for decades, and it was unclear what impact time might have had on the cells.

The experimental gene therapy, ATSN-101, developed by Atsena Therapeutics of Durham, North Carolina, was injected via three incisions near the iris. Researchers tested three dosage levels on three adult cohorts of three patients each, then gave the high dosage to one adult and one pediatric cohort, also three apiece, allowing analysis of 12 patients who received the high dosage. As it turned out, only the high dosage produced significant results.

They were formally followed for a year. Study findings were published Sept. 7 in The Lancet.

People with normal vision can see in a wide range of lighting conditions, from bright sunny days to nights lit only by stars. LCA1 diminishes that range. The gene therapy improved vision mainly in dim light, but the improvement was substantial.

“In as little as 8 to 10 days after the injection, on average, we saw a 100-fold difference, which is probably the difference between standard office lighting versus a restaurant,” said lead study author Artur V. Cideciyan, Ph.D., M.S., a research professor of ophthalmology and co-director of the Center for Hereditary Retinal Degenerations at Penn’s Scheie Eye Institute, in a STAT Q&A.

In two of the nine patients who received the highest dose, the difference was 10,000-fold. “Basically, it’s the difference between an office lighting environment and being able to see with a moonlit sky. It’s quite substantially changed,” Cideciyan said. But he later said that he’d hoped for larger improvements in day vision as well.

Cideciyan said in the STAT interview that the eye, and specifically the retina, is an ideal site for gene therapy. It can be seen in real time, non-invasively, and the primary function of the cell can be measured directly. The region is also the tissue with the most kinds of gene problems that cause blindness. “So all of that allows for an exciting area of research,” he said. “There are also dogs that go blind for the same reasons that humans go blind, so that allows for multiple species comparisons for the same genetic problem.”

Atsena Therapeutics said in news release it plans to pursue a future randomized, controlled Phase III trial for its ATSN-101. The company is developing two other drugs to prevent or reverse types of inherited blindness, and it recently raised about $24.5 million in private investment, according to STAT, following a $55 million Series A round of venture capital raised in 2020.

The just-published study was originally funded by Sanofi and currently funded by Atsena Therapeutics. Both collaborated with investigators on the study design, and Atsena was also involved with the plan for data analysis and data interpretation, writing of the manuscript and the decision to submit it for publication, according to The Lancet article. Three of the 18 authors work at Atsena and another two are members of its clinical and scientific advisory board.

One of the study’s Penn co-authors, Tomas S. Aleman, M.D., co-led another phase I/II trial that reported promising results using CRISPR-Cas9 gene editing to restore sight in pediatric patients with a different form of LCA in the New England Journal of Medicine in May.

“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,” said Aleman, an ophthalmologist at Children’s Hospital of Philadelphia and the co-director with Cideciyan of the Center for Hereditary Retinal Degenerations, in a Penn news release.

Karolinska trial for patients with RLBP-1 associated retinal dystrophy

Bothnia dystrophy, an inherited disease that leads to progressive visual impairment, especially in dim light, due to the destruction of the visual cells in the retina, is caused by mutations in the gene Retinaldehyde-binding protein 1 (RLBP1). Impairment typically begins in early childhood and reaches legal blindness by middle age.

Although it is rare in much of the world, prevalence has been estimated at one in 4,500 residents of northern Sweden.

Anders Kvanta, M.D., a professor and senior physician at Karolinska Institutet’s St. Erik Eye Hospital in Stockholm, and colleagues mainly from Karolinska and Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, led the clinical trial involving 12 patients injected with an experimental gene therapy named AAV8-RLBP1.

Drug-related toxicity was seen mainly at the higher of four dosages tested but there were no serious side effects, according to study findings published Sept. 10 in Nature Communications. All four dosages yielded similar results, with 11 of the 12 patients experiencing significant improvement in vision with low light levels.

The next step would be a larger study with a placebo-treated control group.

The trial was sponsored by Novartis Pharma AG, which also was involved with database monitoring. Eight of the 14 authors are Novartis employees.