The Retina International World Congress 2024 happened last week from 5th-8th of June in Dublin, Ireland. The setting was very rich – and my favourite to be honest – industry and patient representatives, officers from high profile funders for ophthalmic research, clinicians and laboratory scientists. I am not sure there were people working for the regulatory agencies, but hopefully they slowly start to show up more often in these meetings given they are the ones making the decisions on which drugs to approve, discontinue, etc. There were many amazing talks, many of which were in pre-clinical work, so it is impossible to cover them all. Below is a short summary of some of the most promising things in humans (or the ones which are in a more advanced stage in humans).
Gene editing for Leber Congenital Amaurosis
Dr Mark Pennesi from the Casey Eye Institute/Oregon Health and Science Institute in the USA presented the data from a clinical trial for patients with Leber Congenital Amaurosis (LCA) due to mutations in a gene named CEP290. This disease is a quite severe form of generalised retinal disease affecting the light sensitive cells, which we call photoreceptors, that process the photons of light that comes into our eyes, sending this information as electrical activity to the brain. Mutations in this gene are responsible for 15-20% of all cases of LCA. CEP290 has indeed crucial functions in the photoreceptors, with affected children having a severe loss of vision from birth.
The researchers used a quite sophisticated form of genetic therapy named gene editing. This technology uses a system called CRISPR-Cas9, which originated from a type of bacteria that protected it in their aeon-long war with viruses. It essentially cuts a piece of genetic information and removes it from the genome, or introduces a desired segment without any mutation in. I honestly think this is the future of precision medicine, but that’s a story for another time. We talked all about gene therapy in a podcast episode, so feel free to check it out if you’d like to learn more about this.
Anyway, the name of the investigative drug in this clinical trial was Edit-101. It uses a common type of vessel (or vector as we call) to delivery this information to the nucleus of the cells, a virus named adeno-associated viral vector. This is delivered below the retina (in the “subretinal”) space after a surgical procedure named vitrectomy. This trial was named BRILLIANCE, and it was an early phase I/II dose-escalation study, which means that the investigators were still trying to define the dose in a safe manner by starting in a low dose and escalating the dose slowly. We also have a podcast episode about phases of drug discovery that may make this concept a bit clearer if you’re interested.
The results were very encouraging with just a few patients having adverse events, suggesting that Edit-101 was well tolerated. There were also some early signs of efficacy, with more than 70% of patients treated having some sort of improvement in one of the parameters used to measure the function of the retina. Highly successful proof-of-concept that CRISPR-Cas9 indeed can work for retinal diseases. The study did not move onwards to a later phase study due to a business decision of the sponsoring company.
Gene-agnostic therapeutic approaches
Dr Daniel Chung, chief medical officer of SparingVision talked about the company’s approach to treat inherited retinal diseases (IRD) in a more “non-specific” way. You see, most IRDs are inherited as Mendelian monogenic conditions, meaning that typically one gene is involved in that specific disease that the patient has. Some genes such as ABCA4 – the gene that causes Stargardt disease – are quite common, whereas others are so rare that only a few cases have been reported. And gene supplementation therapies (listen to the episode embedded above for full clarity) are used to supplement diseases affected by mutations in a single gene. It is not very feasible for biopharmaceutical companies to take the initiative to start testing a new drug for a very rare disease, in an extremely long process (usually more than 10 years from discovery to market approval), to in the end be able to treat a very limited number of patients; it’s the crude reality.
What SparingVision is attempting is a really cool new strategy in which the gene would not matter, given they would target a common pathway to inherited retinal diseases. Their currently ongoing trial, PRODYGY, is another early phase I/II using a molecule named rod-derived cone viability factor. It is active and currently in their third dosing cohort. We in the research community are extremely hopeful for treatments such as this, given this is likely to offer patients another option for treatment in the future, a more generic one for the lack of a better term. Godspeed to their team!
The Eye2Gene project
Dr Wiliam Woof, lead artificial intelligence (AI) engineer of this project, talked about this very interesting work using AI and deep learning (DL) tools to try and predict which inherited retinal disease the patient has, and specifically which gene is likely to be affected. Essentially, an algorithm is used to create a model that is able to do this, which is trained in (literally) many thousands of a couple of retinal imaging modalities. How cool is that? Small disclaimer: I am certainly biased in this “coolness” given I am participating in this study myself too. Give the project a read on this link.
The preliminary results are remarkable and outweigh even the best of specialised clinicians with more than 25 years of experience. One thing mentioned by Dr Woof, which I found really relevant, is that this is not to say that the clinicians are not doing an amazing job, but it is just that the computer can see things that the human eyes can’t; it’s as simple as that. On some instances, the model performed more than two times better than humans. This project has the potential to democratise genetic testing by suggesting the most relevant genes to test, which has major impact in the costs of testing in the “real world”.
Other mentions
From using CRISPR-Cas9 to create animal models of diseases, to refining how we assess the function of the retina (which by the way has direct implications in clinical trial development), there were many other very interesting talks with leaders in the field. There were panels and committees formed with patient representatives; for me, this is the most important section of the conference and why I love this type of meetings.
But I should also mention that there was a very nice choir with blind patients in the morning of the 8th. Quite emotional and such a privilege to being able to see this group of extremely talented singers. Afterwards, there was a very cool live podcast episode with the nice folks at The Blind Guys Chat. This was a very nice concept, and I loved that the organisers introduced this to the program. Check them out in this link.
Being able to go attend conferences, or watch it remotely, is a privilege. Many of the new (and sometimes preliminary) research updates come first in conference because it takes time for the research groups to have the full data, analyse it, write and publish a full scientific paper. My aim is to do some onsite interviews in the next conference, but let’s see how that goes. Let me know if that’s something you would enjoy.
I will see you later!
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Thales A. C. de Guimaraes, MD, PhD
Host and Founder | Eyes On Research