Stem Cell Grafting in Parkinson Disease: Feasibility, Safety, and the Path Toward Proof of Concept

Despite decades of therapeutic advances in Parkinson disease (PD), all currently available treatments remain symptomatic. Dopaminergic therapies such as levodopa and deep brain stimulation can improve motor function, but none slow or reverse the underlying neurodegenerative process driven by progressive loss of dopaminergic neurons. The concept of replacing these lost neurons has long been a goal of translational neuroscience, though earlier fetal tissue transplantation efforts yielded mixed results and raised safety concerns, including graft-induced dyskinesia.

Advances in induced pluripotent stem cell (iPSC) technology have renewed interest in restorative strategies. iPSCs, generated by reprogramming adult somatic cells into a pluripotent state, can be differentiated into dopaminergic progenitor cells suitable for implantation. These next-generation products aim to improve standardization and cellular fidelity compared with earlier graft approaches, with preclinical studies demonstrating dopaminergic differentiation, survival, and integration within basal ganglia circuitry.

Keck Medicine of USC is participating in the phase 1 REPLACE trial evaluating RNDP-001, an iPSC-derived dopaminergic progenitor cell therapy manufactured by Kenai Therapeutics. Xenos Mason, MD, a movement disorders neurologist at Keck Medicine and coinvestigator of the study, discussed the early significance of this first-in-human trial, safety considerations including dyskinesia risk, and the translational framework guiding patient selection and outcome assessment.

As an early-phase trial, what is the main significance of this study in demonstrating feasibility, safety, and proof of concept for iPSC-derived dopaminergic cell therapy in Parkinson disease?

Xenos Mason, MD: Multiple recent studies involving embryonic or IPSC-derived stem cell products together demonstrate that these trials are feasible. As a clinical specialist and advocate in Parkinson disease, I also observe that the community has a deep and sustained interest in stem cell therapies, and holds much hope surrounding the potential for this strategy to offer symptom improvement and disease modification. So we had little doubt regarding feasibility.

Our primary focus during this initial phase is safety. As a first-in-human trial, our scrutiny of safety data and outcomes in each subject is extremely strict. We monitor each subject carefully.

The biological “proof of concept” is the next crucial step: Do the cells survive? Do they become functional? How can we understand the effect of a stem cell graft on local and distant brain circuitry? We hope these are unanswered questions will drive further refinement of stem cell products and implantation techniques. Our protocol is designed to collect data that will determine patient response at a granular functional level—both motor and nonmotor outcomes— and then correlate these with neuroimaging biomarkers of graft function.

Given past concerns about dyskinesia with dopamine cell therapies, how does this study monitor and assess potential graft-induced dyskinesia and other neurologic adverse effects?

Please see: Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease

Also, for a summary comparing autologous and allogeneic strategies: Advantages and challenges of using allogeneic vs. autologous sources for neuronal cell replacement in Parkinson’s disease: Insights from non-human primate studies

Dyskinesia has historically been a concern with cell-based dopamine therapies. How is this study structured to monitor for and characterize potential graft-induced dyskinesia or other neurologic adverse effects?

This was and remains a significant safety concern in the new era of stem cell trials. There is preclinical data to suggest that serotonergic differentiation of fetal-derived stem cell grafts was in part responsible for dyskinesia, and that IPSC-derived dopaminergic progenitor cell grafts will show little to no serotonergic differentiation. This aside, we assess for dyskinesia throughout the follow-up period using home diaries and both clinical and instrumented outcome measures. Without divulging nonpublic aspects of the protocol, I can say that we are using multiple objective and subjective methods to assess for dyskinesia.

What were the key considerations in selecting patients with moderate to moderate-severe PD for this trial, and how might disease stage influence outcomes?

We looked for patients with clear and measurable symptom burden and some period of daily off time, normal cognition, and a stable medication regimen. But most important was receptiveness to the clinical protocol, which is demanding of time over many months and with many rounds of clinical assessment. A clear and nuanced understanding of risks and benefits was also crucial, as was an understanding that this was a first-in-human trial that was uncertain to have any clinical benefit. Simply put, we prioritized informed and educated participation. Otherwise, we have precious little clinical data to guide our a priori expectations. At this point, for example, we have no reason to believe that outcome will be correlated with measures of disease severity, such as UPDRS scores, disease duration, or medication dosing [levodopa-equivalent daily dose]. Gait and balance symptoms tend to occur later in disease and limit rehabilitation and so needed to be considered carefully when planning this surgical trial.