One-Year Survival of Transplanted Cells Marks Progress in Early Retinal Regeneration Studies

What is RP?

RP is one of the most common types of inherited retinal disease (IRD), associated with faults in over 100 genes, affecting around 1 in 4,000 people globally. RP causes progressive vision loss, starting peripherally, due to the loss of light-sensing photoreceptor cells in the retina. To learn more, please watch this short animation video on Inherited Retinal Disease

There are a number of investigative treatments in development for RP that use a variety of therapeutic approaches such as gene therapy, cell therapy and optogenetics. Developing mutation-specific gene therapies for RP remains challenging due to the vast number of genetic causes identified. Unlike gene therapies, which aim primarily to slow or stop further deterioration, some cell-based therapies offer a chance to repair part of the retina and potentially restore some degree of vision. Cell-based therapies such as CNS10-NPC could offer the potential for a gene-agnostic approach that bypasses the genetic cause of the condition and benefit a broader population of our community.

What are Neural Progenitor cells (NPCs)?

The cells being transplanted into the retina in this trial are called neural progenitor cells (NPCs), a type of stem cell. NPCs are immature cells found in the brain, spinal cord and retina that can develop into different types of nerve cells and supporting cells. They play a vital role during early development by helping to build the nervous system and a small number remain in certain parts of the adult brain where they contribute to limited repair and the production of new nerve cells.

Scientists are investigating their use in regenerative therapies to help protect or replace damaged cells in diseases affecting the brain and eyes. This is because they can replace cells that have died or become damaged, release growth factors that help existing neurons survive and reduce inflammation. This makes them promising candidates for treating conditions such as inherited retinal diseases. However, these particular cells cannot become light-sensitive photoreceptors and will not directly repair areas of degenerated retina.

What is CNS10-NPC?

The neural progenitor cells used in this trial were derived from foetal brain cortex because this source produces cells that are highly adaptable, survive well after transplantation and have shown promising protective effects in earlier animal studies of retinal degeneration. As the retina is part of the central nervous system, developing from the same embryonic tissue as the brain, cortical neural progenitor cells can survive in the retinal environment and provide supportive signals to retinal neurons.

NPCs can develop into the three major cell types of the central nervous system. In this trial, the cells are called CNS10-NPC and have been derived to specifically become astrocytes. Astrocytes in the eye help to keep nerve cells healthy by supplying nutrients, regulating the chemical environment, reducing inflammation and supporting tissue repair. At this stage, researchers believe their main benefit is creating a healthier environment for the surviving retinal cells, potentially slowing the progression of the disease. Whether they can ultimately restore vision remains an open question that larger, longer-term clinical trials will need to answer.

Preclinical studies showed that CNS10-NPC preserved photoreceptors and vision in animal models through reducing inflammation and the release of powerful growth factors, supporting its evaluation in people.  This trial is the first to use a human progenitor cell line to treat retinitis pigmentosa in people

The trial:

This Phase 1/2a clinical trial evaluated the safety and feasibility of a single subretinal injection of CNS10-NPC in 13 participants with RP. It was a single-centre, open label, safety study of two escalating doses of human neural progenitor cells. This means that both participants and researchers knew who was getting which treatment dose and there was no placebo group. It also means that the dose was gradually increased across groups of participants. In early-stage clinical trials, this is common because the main focus is on safety and trying to identify the dose that is the most effective and safe.

Participants received either 300,000 or 1,000,000 cells and were followed for 12 months and then enrolled into a long-term follow-up study.

Results:

Visual acuity remained stable throughout the study, and imaging demonstrated that transplanted cells remained present in the subretinal space for at least one year. Due to the natural progression of RP, changes in vision were not expected during the first year of the study. However, investigators continue to follow participants to determine whether long-term survival of the transplanted cells can help preserve vision in the treated eye over time.

Cell-related adverse events included three epiretinal membranes (thin layers of scar tissue that form on the surface of the retina) and one persistent subretinal bleb (a small pocket of fluid deliberately created beneath the retina during subretinal injections). Overall, investigators concluded that the treatment was well tolerated.

“This study represents the first demonstration of long-term survival of foetal-derived neural progenitor cells in patients with retinitis pigmentosa while maintaining a favourable safety profile. Long-term engraftment is a critical milestone for the development of stem cell-based therapies for retinal disease and provides an important foundation for future studies.”- Clive Svendsen, Ph.D., Cedars-Sinai Board of Governors Regenerative Medicine Institute, USA and sponsor of the project

What next?

“Our goal is to help patients maintain their vision for as long as possible. The next critical question is whether these surviving cells can slow the continued deterioration that occurs in retinitis pigmentosa.” – Dr. Liao the clinical lead on the project.

Svendsen also presented data on an induced pluripotent stem cell (iPSC)-derived neural progenitor product during the presentation. The adult cells used for iPSC generation can be easily and cost-effectively obtained, and iPSCs are now used routinely to create retinal tissue as a model for laboratory-based research.

An iPSC-based approach could provide a more scalable therapy capable of treating substantially more people in the future while avoiding ethical concerns associated with foetal tissue sources.

We look forward to hearing the exciting updates from this research as it progresses! For more information about the trial, please visit the following website https://clinicaltrials.gov/study/NCT04284293