Morning light streaming through the windows often jolts people awake who forget to close their curtains the night before. But for kids with the ultra-rare aryl-hydrocarbon-interacting protein-like 1 (AIPL1)-associated severe retinal dystrophy — a condition referred to as AIPL1 — the bright morning beams don’t typically bother them at all. While they can perceive light, they tend to keep their eyes closed most of the time, moving through the world by touch.

But when Michel Michaelides, an ophthalmologist and researcher at University College London who was testing a gene therapy in these kids, started to hear from parents that the morning light now bothered their children, he was skeptical.

“We were getting reports from the family — emails, videos, texts — saying, ‘I can't believe it. They can see this. They've never been able to see that,’” he said. As a clinician, he added, “you want to be convinced. You don't want to — just because you want it to work — believe it's working.”

After measuring their vision and running multiple other tests on the kids in two very unique, first-in-human studies of a gene therapy for AIPL1, Michaelides believed it; they really could see the world around them (1). Now, he and his collaborators at MeiraGTx, with whom he developed and manufactured the gene therapy, hope to get the therapy approved and out to as many patients as possible because with AIPL1 — there’s no time to lose.

Responsible for supporting enzymatic activity in the photoreceptor cells in the retina during development, AIPL1 is a vital protein for vision (2). When its function is impaired due to mutations, the rods and cones in the retina degenerate, leading to progressive vision loss (3). The condition has no treatment.

For a long time, clinicians were convinced that these young children were so visually impaired that no therapy could possibly help them see. Doctors worried that without functioning photoreceptors, the brain would never learn to interpret visual information.

“They’d say, ‘Oh, there's no reflex at the retina. Oh, there’s no retina,’” Michaelides said. But he decided that he was going to look closely at these children’s retinas to be absolutely sure. “It's really hard to examine children whose eyes are going like that,” he said, pointing his fingers in opposite directions, but “just because it's hard, it doesn't mean we shouldn't do it.”

Young kids can’t sit still and rest their chin on a typical optical coherence tomography (OTC) machine to analyze their retinas as easily as adults can. So, Michaelides used a hand-held OTC and took a video of their eyes for about an hour, giving him more opportunities than a single still image to capture the part of the retina that he needed to see (4).

Contrary to prior thought, Michaelides found that there were photoreceptor cells in these kids’ retinas. “Not many,” he said, “but there's an absolute hill of retinal cells in the center of the retina.”

Altogether, he and his team assessed AIPL1 patients ranging from six months to 43 years old. But, after age four, they saw that the retina completely degenerated. This meant that for a therapy to restore sight in these children, clinicians had to not only find these ultra rare patients, but they also had to find them between birth and their fourth birthday — a tiny window of opportunity.

But MeiraGTx was prepared. They had what’s called a “specials” license from the Medicines & Healthcare products Regulatory Agency (MHRA) in the UK. This license allows a company to produce a medicine up to Good Manufacturing Practices standards and provide it to doctors free of charge to treat patients with rare degenerative disorders that have no other treatment options. With Michaelides, they had developed an adeno-associated virus (AAV)-based gene therapy expressing a healthy copy of the AIPL1  gene.

“It's not a conventional clinical trial,” said Michaelides. “It's not compassionate use. It's ‘specials,’ and unless you know about the MHRA, this is totally novel. FDA [and] EMA don't have this route.”

With positive results of the gene therapy in animal models, Michaelides and his team then just had to find their patients (5). Eventually, they found two children from Turkey, one from Tunisia, and one from the United States aged between one and three. Because it was the first time giving this therapy to anyone, the researchers only treated one of their eyes, but they did treat the better of their two eyes to give the kids the best shot possible at improving their vision.

“We were astounded by the improvements we saw,” Michaelides said. Not only were the safety readouts great, but the children went from only responding to bright light to having on average 20/200 vision. “20/200 to you may sound, well, that's not brilliant, is it? No, that is brilliant. That's awesome. If I take my glasses off, I don't have even 20/200 vision, so it's fantastic vision when your vision is bare perception of light.”

With this level of visual acuity, these kids don’t need to attend a school for the blind, and they can more easily engage with their peers and the world around them.

Because the therapy worked so well, the team decided to treat seven more children in both of their eyes this time. In these seven kids, the therapy was safe and worked just as well as before, Michaelides and MeiraGTx reported in a February press release.

“Now it's all 11 [who can see], so even that in itself is kind of ridiculous — but wonderfully ridiculous,” Michaelides said.

The next step now is approval. The MHRA told Michaelides that they have seen enough clinical data to move the therapy down the exceptional circumstances approval pathway, and he and MeiraGTx have so far had positive conversations with the FDA and EMA about the therapy as well.

“It's probably going to take 12 months, probably at best, and we know during that one year, there'll be children that will become five, as it were,” Michaelides said. “We feel it deeply, and I think the regulators get it as well. So, it's as fast as we can get it approved.”

For now, Michaelides is sharing the results from these unique clinical studies with the world. Even though he’s already seen the videos of the kids before and after receiving the gene therapy many times, he is still amazed by how well they can now see.

“I know what's in the video, and it's still emotional!” he said. “It's unbelievable in the literal sense.”

References

1. Michaelides, M. et al.  Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study. Lancet  405, 648-657 (2025).
2. Gopalakrishna, K.N. et al.  Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client. J Biol Chem  291, 16282-16291 (2016).
3. Kirschman, L.T. et al.  The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells. Hum Mol Genet  19, 1076-1087 (2010).
4. Aboshiha, J. et al.  Preserved Outer Retina in AIPL1 Leber's Congenital Amaurosis: Implications for Gene Therapy. Ophthalmol  122, 862-864 (2015).
5. Tan, M.H. et al.  Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Hum Mol Genet  18, 2099-2114 (2009).