Cell therapy approaches goal of restoring vision in geographic atrophy – Healio

A cell replacement therapy that uses retinal pigment epithelium-derived stem cells is showing the potential to restore retinal tissue in advanced age-related macular degeneration with geographic atrophy.
“When we designed the trial, our aim was to stop or slow down the progression of geographic atrophy (GA), and much to our surprise, we found that this therapy not only prevented progression but restored the outer retinal layer. This is a tremendous milestone, a real breakthrough, something that has not been seen ever,” Jordi Monés, MD, PhD, director of the Institut de la Màcula and Barcelona Macula Foundation, told Ocular Surgery News.
OpRegen cell therapy (Lineage Cell Therapeutics) is currently being evaluated in a phase 1/2a open-label international safety and efficacy study. Interim results on 20 patients showed slower GA growth over 2 years and visual acuity improvement in a subgroup featuring better baseline vision and smaller areas of GA. On high-resolution OCT, the presence of new areas of retinal pigment epithelium (RPE) monolayer that were not present at baseline was observed, suggesting integration of the new RPE cells with functional photoreceptors in areas that had been deprived of them by the disease.
“In previous studies with stem cells, what could be seen was pigmentation under the retina, which was never proven to be viable cells. They were probably cell clumps, debris accumulated under the retina. In this study, we were able to see on OCT something entirely different. The RPE cells we inject are able to induce changes — new RPE monolayers with new overlying ellipsoid zone (ELZ), external limiting membrane (ELM) and outer nuclear layer (ONL), which is really RPE doing its job,” Monés said. “The highest achievement of previous trials had been a 25% reduction of GA growth rate, meaning that the best scenario was a 75% growth every year. This treatment has shown potential to stop growth entirely and to have the retinal function restored. One of our patients has had no growth for 3 years.”
It is relatively easy for skilled retina surgeons to perform this procedure, according to Monés. After vitrectomy and hyaloid peeling, a suspension of RPE cells derived from an established pluripotent cell line is transplanted subretinally through a small retinotomy with a single injection.
“The main challenge is to avoid reflux into the vitreous cavity because these RPE cells have a lot of capacity to contract and form epiretinal membranes,” he said.
An alternative technique uses the Orbit subretinal delivery system (Gyroscope Therapeutics) to make an entry through the sclera into the suprachoroidal space. A cannula is advanced posteriorly toward the target area of atrophy in the macula, and a needle is advanced through the choroid to deliver the cells into the subretinal space without perforating the retina.
“Both techniques have pros and cons. With the transvitreal retinotomy, you deliver the cells exactly where you want, but you have the problem of reflux and epiretinal membrane formation. With the suprachoroidal method, you don’t have this problem, but it is slightly more cumbersome to deliver the cells where you want. It is too early to know which of these methods is the best. More cases and more time will tell,” Monés said.
Treating GA is a challenge because it is a battle against degeneration, aging and death.
“What we are trying to do is change the biological clock of cells and resuscitate a dead retina, which may seem like an impossible task,” Monés said.
The goal of getting to the root cause of GA, and from there finding the key to revert the degenerative process, motivated him to research regenerative cell replacement methods. As a leading independent expert in this field, Monés was asked to contribute to the design of the OpRegen trial, identify the phenotypes that could benefit the most from this treatment and pin down the features of retinal restoration.
“One of the important criteria we established was that every patient we enter in the trial should have historical data on GA growth for at least the 6 previous months, well documented on imaging. This enables us to calculate the theoretical growth without treatment at any point in time and compare it with the actual growth with the treatment. If you have an idea of how that particular eye would have behaved without treatment and then see that the treatment is changing the natural history, that is very meaningful,” Monés said.
Another important decision was to use OCT rather than autofluorescence to identify cellular changes in the retina.
“Autofluorescence is the most conventional way to measure atrophy, but in this case, it does not work at all because these cells have not had time enough yet to accumulate lipofuscin, so they do not autofluoresce. They appear as dark spots; you think you have atrophy and instead you have cells,” Monés said. “On the other hand, hypertransmission of OCT does not work because when we put something extra under the retina, this material may interfere with the signal. Therefore, we needed to use a combination of imaging techniques, relying on histology and on the correlation of histology with OCT. We started to define very fine details in the outer retinal layers, and this has been most of my work, to identify these changes, analyze every single patient and every single potential side effect, and advise the company on the next steps.”
A key feature of the success of Op-Regen therapy is the regeneration of the ELM, ELZ and ONL, absent in the area of disease in patients with GA. The ELM is the junction between photoreceptors and Müller cells and has been used as the biomarker to measure GA size. Regeneration of these layers means that those cells are not only restored but are connected.
“To have objective evidence that those cells are functioning, we should perform functional tests, but the current study is not powered for that, and we are waiting for the next phases of the trial. However, the study eyes have maintained or in some cases even regained vision, while the fellow untreated eyes have lost vision over 3 years, and the difference is quite astounding,” Monés said.
Retinal restoration is the holy grail of GA. Patients at that stage of AMD have had no options so far, even for the more modest goal of slowing down growth rate.
“Now we can raise the bar toward the ambitious goal of reverting the process and improving vision. It is a completely new world, a new dimension, giving hope back to our AMD patients,” Monés said.
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