Seven years after the FDA approved Luxterna, scientists have yet to bring another congenital blindness treatment to the market.
A team of researchers from the Perelman School of Medicine at the University of Pennsylvania aims to change this. The group recently published a study in The Lancet documenting their success using gene therapy to treat an inherited retinal blindness that affects as many as 100,000 people globally.
Targeting people with a variant of Leber congenital amaurosis (known as LCA1) — a kind of vision loss not easily corrected with glasses — the researchers injected 15 people with ATSN-101, the experimental gene therapy. Participants’ vision on average improved and lasted for the duration of the observation period (12 months), with no serious side effects observed.
For people without an inherited retinal blindness, the typical range of vision works over a very large range of lights, from a piercingly sunny day in Florida to a starlit night. The human eye can see in those two extremes as well as anything in between. But for people with LCA1, that range is severely diminished.
Lead study author Artur Cideciyan is quite optimistic about the study’s results, even with the limited sample size. STAT spoke with the ophthalmologist and co-director of the Center for Hereditary Retinal Degenerations at Penn about the findings and how he sees the field, especially in light of recent work from one of the study’s co-authors, in which they successfully used CRISPR-Cas9 gene editing to treat a different form of LCA.
Atsena Therapeutics developed the gene therapy used by the authors. 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, following a $55 million Series A round of venture capital raised in 2020. Atsena plans to pursue a future randomized, controlled Phase III trial for ATSN-101.
What’s the topline findings from this study that injected ATSN-101, a gene therapy, into people with inherited retinal blindness?
The key question we were asking is whether this gene therapy was safe. And it is safe. We were also looking at whether the therapy was changing the vision of the patients who are otherwise blind or visually disabled. And what we found is that at the high dose, there is a very large and substantial improvement in the ability to see dim light.
What kind of response did you see from the participants?
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. This is on the dim end of ambient lighting that we use in human environments. In two [out of the 9 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.
There were 68 adverse events. If safety was one of the main concerns here, why should we ignore those events? How do we know that these aren’t problems related to gene therapy?
The one macular hole, that means that part of the retina formed a hole after the surgery. That’s a well known, rare side effect of these surgical procedures. Same with the bacterial infection, that is a well-known, rare side effect of ocular surgery. So some of these findings have happened before with different drugs and the consequence of the same surgery with different drugs. Thus it is unlikely that it is due to the drug.
Mechanistically, how does this gene therapy target the disease?
In LCA1, the gene causes dysfunction in the eyes’ photoreceptor cells. However, the cells are retained structurally over many decades. Even after that time, there is the potential for being able to turn the cells back on, if you will. We use gene therapy, or more exactly gene augmentation therapy, to send a virus to provide the missing enzyme to the cell. The virus acts as a carrier or a truck that carries the missing enzyme into the right cells. If everything else in the cell is still there after decades of vision loss, then in theory the cells can restart the process of seeing and provide vision to the patient.
Why is LCA the main kind of inherited retinal blindness that people are targeting?
At a very top level, the common theme of all LCAs — and there are at least 20 different genetic types — the common theme is either they are congenital or early onset blindness. Both photoreceptor types, the so-called rods and cones, are not functioning from very early on. Often, it means that it’s a disease of dysfunction as opposed to degeneration. That opens the door that one can perform gene therapy and turn them back on. Which is very different from progressive retinal diseases, which are the majority of congenital retinal diseases. An important part of the treatment strategy for those would be to stop or slow down the progress of degeneration, which is a different kind of a strategy and is more difficult to measure. As opposed to this condition, for example, where in a matter of days, there are major changes.
Any other findings from the study you’d like to mention?
The size of improvement occurred with night vision compared to improvement in day vision. There was previous evidence that night vision improvement was easier to achieve or larger in magnitude than day vision improvements. It turns out to be the case in this form of the disease. That was a surprise. We were hoping for larger day vision improvements but that remains rarer and less understood.
Why does it matter to get better day vision?
Day vision drives color vision, it drives our typical environments which are artificially lighted almost all the time. In a typical western human life, day vision is more useful. Now night vision can act and does act within day vision conditions, counterintuitively. When somebody doesn’t have day vision, night vision takes over, but it doesn’t do as good a job and does not provide color vision. The ideal would be improvement of both.
Why is the eye a good site for gene therapy?
The eye is an excellent site for gene therapy for several reasons and specifically the retina. We can see it in real time, non-invasively. We can measure the primary function of the cell, directly. The retina 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. 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.
You started working in this field in 1989. Is this where you expected the field to be, 35 years later?
One can actually argue that it has moved slower than imagined. When the first success of retinal gene therapy came about in 2008, and there were three simultaneous studies on three independent groups, and they were all on the same disease and they were all positive — one imagines that success would be duplicated in other types of blindness. We are coming to almost 15, 20 years after that and Luxterna remains the original retinal gene therapy and there’s been no second one. Obviously, it’s not easy to extrapolate from one disease to another, they’re all different mechanical causes and present their own challenges and we hope that there will be some more approved treatments. But progress has been slower than expected.