Children born with Leber Congenital Amaurosis, or LCA (specifically LCA-AIPL1), a severe and rare form of blindness inherited from their parents can now have new hope.
Researchers at Moorfields Eye Hospital London have made a breakthrough in their collaboration with MeiraGTx. They also worked closely with University College London. The innovative gene therapy they developed has been proven to be safe and effective, not only in improving the vision of young patients with LCA AIPL1, but in also slowing down retinal degeneration.
LCA AIPL1 is a rare, aggressive form of Leber congenital apharosis that affects about 2 to 3 babies out of every 10,000,000. The condition can cause severe visual impairment, or complete blindness. Affected children experience delays in important developmental areas such as behavior, communication, and mobility.
The results of the groundbreaking clinical trials conducted on this gene therapy are astounding. The joy of seeing is now available to children who previously only explored the world by touch. The children can navigate the environment confidently, identify objects and images, and take part in activities such driving go-karts.
Leber congenital apharosis is a grouping of retinal dystrophies affecting the retina. The retina contains photoreceptors and it’s the tissue that detects light at the back part of the eye. These disorders affect roughly 2–3 out of every 100,000 births. Mutations in genes that are crucial to the development of the retina cause the various forms of LCA.
The only LCA form that is currently treatable involves mutations of the RPE65 genes, which code for a key protein for the visual cycles. The protein is responsible for regenerating the pigments of photoreceptors cells. It allows the cells to convert light signals into electrical ones that are interpreted by the brain as sight. RPE65 disrupts the visual cycle, which leads to vision impairment. LCA-RPE65 is associated with poor vision at night and daytime acuity in children.
Luxturna is a gene therapy approved by the U.S. Food and Drug Administration in 2017. It was developed specifically to treat RPE65 associated LCA. A viral vector delivers a healthy copy a gene that has been mutated into the cells of patients. It helps to restore correct protein production, and addresses the genetic causes of disease.
RPE65 mutations are responsible for a very small number of LCA cases (approximately 8%) RPE65 associated LCA is less severe than other types of LCA and tends to progress more slowly. It allows for an extended treatment period, as the patients are eligible for gene therapies even after they have been diagnosed in their 30s or 40s.
This groundbreaking research focused on LCA AIPL1, which is one of the most difficult and rare forms of LCA. LCA AIPL1 occurs when the AIPL1 gene is mutated. This is crucial for the growth and function of the photoreceptors. LCA AIPL1 is associated with a severer visual impairment in children, especially when low-light conditions are present.
Babies with LCA AIPL1 can have roving movements of the eyes or be unable to fixate their gazes on faces or objects. Sleep disturbances may be experienced due to the disruption of their circadian rhythms. The visual problems can have a significant impact on orientation and depth perception.
LCA AIPL1 presents a more limited treatment window than RPE65. The limited retinal function tissue rapidly degrades after the age of 4, resulting in complete and irreversible blindness. It is important to act quickly and diagnose the condition early.
Professor Michaelides’ team published a report in The Lancet detailing their successful gene therapy trials involving 4 children who had LCA-AIPL1. Each child received gene therapy in one eye, and the other was left untreated as a comparison control.
In order to access the retina, the surgical procedure involves removing the vitreous (a substance similar to gel) gel from the eye. A viral vector with healthy AIPL1 gene is then injected under the retina. This allows the virus to transmit the genetic code for photoreceptors.
Initial improvements in the vision can be seen within a few weeks. The long-term results of the study, which took place three to four year after gene therapy, showed that untreated eyes had a significant loss in vision, while treated eyes improved.
Michaelides said that the patients “went from barely perceiving a light to recording it on a graph.”
The patients were able read the first line on a normal eye chart. This meant that at 20 feet, they saw what a person who has normal vision would see at 200. In the past, researchers have treated another seven LCA AIPL1 children with both eyes receiving gene therapy. All children showed impressive improvements in vision. One child achieved 20/80.
“The fact that all eleven benefit—it’s genuinely remarkable,” said Professor Michaelides.
Researchers are currently in discussion with regulators, such as FDA, from the U.K. and Europe. They also have discussions in the United States. The researchers expect the FDA to approve the treatment for wide-scale use in the next year or two.
Although the durability of the improvements is still being investigated, Professor Michaelides remains optimistic that the benefits could last a lifetime.
He said that even if vision improvements aren’t long-lasting, they will still have a profound impact on other areas of development, including communication, mobility and behavior.
Bradley and Jessica Haines witnessed the benefits of gene therapy first-hand when their son Harvey received it in both his eyes. Harvey was unable to make friends in new environments before the gene therapy.
Bradley said that “pre-surgery he liked to be around older kids or adults.”
Jessica continued, “He often came home and told us that he had played with a school teacher. This was concerning to us because we wanted our children’s friends.”
Jessica observed significant changes after Harvey’s surgery. She noted improvements in the interactions between Harvey, his brothers, and their parents. “For the first time, they started playing together, engaging in role-playing games like teachers and airplanes, activities that require vision – something we hadn’t seen before.”
She said: “It is exciting to watch him develop more friendships.”
Refer to the following:
Michaelides, M., Laich, Y., Wong, S. C., Oluonye, N., Zaman, S., Kumaran, N., Kalitzeos, A., Petrushkin, H., Georgiou, M., Tailor, V., Pabst, M., Staeubli, K., Maimon-Mor, R. O., Jones, P. R., Scholte, S. H., Georgiadis, A., van der Spuy, J., Naylor, S., Forbes, A., Dekker, T. M., Arulmuthu, E. R., Smith, A. J., Ali, R. R., & Bainbridge, J. W. B. (2025). A first-inhuman open-label interventional trial evaluating gene therapy for children with severe AIPL1 associated retinal dystrophy. The Lancet, 405, 648–57. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02812-5/fulltext