STEM cell therapy holds promise for treating advanced Parkinson's disease

STEM cell therapy holds promise for treating advanced Parkinson's disease

A stem cell-based therapy originally developed at Memorial Sloan Kettering Cancer Center (MSK).Nature.

The treatment involved creating nerve cells (neurons) derived from embryonic stem cells and transplanting them into the brains of 12 Parkinson's patients.

The injected cells produce a chemical called dopamine, which coordinates movement. Parkinson's patients have abnormally low levels of dopamine and, as a result, suffer from tremors, slowness, stiffness and walking or balance problems.

Cell therapy was developed at MSK in the laboratories of Lorenz Studer, MD, director of MSK's Center for Stem Cell Biology, and Viviane Tabar, MD, chair of MSK's Department of Neurosurgery, before being licensed to Bluerock therapeutics.

The Phase 1 study is a two-year study sponsored and conducted by Bluerock at multiple centers in the United States and Canada. One of the principal investigators for the trial was Harini Sarva, MD, chief of the Division of Movement Disorders at Weill Cornell Medicine.

The researchers found that after 18 months, the injected cells had persisted in the brain without any serious side effects. In particular, some patients appeared to have stabilization or improvement in their Parkinson's symptoms.

Based on these preliminary results, the US Food and Drug Administration (FDA) has granted approval for the direct Phase 3 clinical trial in a much larger patient group. This trial is expected to begin in the first half of 2025.

“This is an important milestone on the path to regenerative brain repair,” says Dr. Tabar, who helped lead the clinical trial and is the first author of the study. "It represents more than two decades of collaborative work, based on very rigorous science, starting in our laboratories. It seems unusual for a cancer center to pursue regenerative medicine for a neurodegenerative disease. However, if we can figure out how to replenish cells lost to disease in the brain, we can expand it to other treatment. Cancer patients benefit."

Turning stem cells into neurons

The researchers created a method for over-exciting embryonic stem cells to develop into early forms of dopamine-producing neurons. They scaled up the process to produce large batches of these cells. The resulting product of identical cells, called BemdaneProcell, can be frozen until used.

This is a big step for the stem cell field - to see these encouraging results of a truly exceptional dopamine neuron product in patients with Parkinson's disease. We are excited to see this movement evolve into a larger, randomized trial. “

Lorenz Student, MD, Director of the MSK Center for Stem Cell Biology

The researchers note that the phase 1 study included a small group of patients and did not have a control arm. The upcoming Phase 3 trial, which includes around 100 people, is expected to produce definitive results as a group of patients will receive placebo treatment. Additionally, Phase 1 patients will continue to be evaluated to determine whether therapy has lasting effects beyond the two years of this study period.

The Phase 3 trial is sponsored and conducted by Bluerock Therapeutics, where Dr. Studer and Tabar are scientific co-founders.

MSK's history of stem cell research for Parkinson's

The Phase 3 study is the culmination of research that dates back 25 years when Dr. Studer first came to MSK and investigated embryonic stem cells as a potential treatment for various diseases. His laboratory has worked for the past two decades with Dr. Tabar's lab, with a focus on the application of stem cell therapy to Parkinson's disease.

Parkinson's disease occurs when the dopamine-producing neurons stop working or die. It is a lifelong, progressive disease in which symptoms slowly worsen over time. It affects nearly 1 million people in the United States and more than 6 million people worldwide.

Over the past 50 years, the pace of treatment has been slow. The main therapy is a drug called L-Dopa, which was first used in the 1960s and was revolutionary at the time. But L-Dopa is not a cure and eventually stops working.

Parkinson's disease has been considered a prime candidate for stem cell-based therapy because it involves degeneration and loss of a single cell type (dopamine-producing neurons) in a specific location - a region of the brain called the putamen.

Starting in 2009, researchers in the Tabar and Studer laboratories made a number of discoveries using embryonic stem cells, which are pluripotent, meaning they can develop into any cell type. The teams found that these pluripotent cells could be reliably targeted to turn into dopamine neuron precursors. They further refined their methods to ensure purity and quality control and conducted repeated testing in animal models.

“For the first study, we could produce the progenitor cells here in the MSK facility under clinical conditions without depending on an external source,” says Dr. Studer. “This allows us to create a very large number of cells that are ready for deployment.”

In 2021 they published two definitive articles in the journalcell stem celldemonstrates the safety and effectiveness of BemdaneProcel in animals. This led to the approval of the Phase 1 trial that opened this year.

Efforts to prevent side effects

In the study, nine patients were transplanted at MSK and three were transplanted by staff in Toronto. The embryonic stem cells come from a donor, so patients who received the dopamine-producing neurons were given a year of immunosuppressant drugs so they wouldn't reject the transplant.

Past studies using fetal tissue as a source of dopamine neurons have had problematic side effects - mainly involuntary movement, called transplant-induced dyskinesia. But the MSK researchers seem to have solved this problem.

“We were inherently concerned about dyskinesias and were very careful in our process,” says Dr. Studer. "One of the very encouraging results was that we saw no evidence with our treatment. Overall, there were no serious side effects from the transplanted cells or the immunosuppression."

A key tool in making the implantation safe was MSK's intraoperative MRI capabilities, which provide live imaging during the procedure. “It allowed us to deliver the cells exactly where they are needed with the lowest possible risk,” says Dr. Tabar.

In the clinical study, two different doses of dopamine-producing cells were tested. Both levels appeared to be safe, but the higher dose appeared to be more effective in improving symptoms. Patients participating in the upcoming Phase 3 trial will receive the higher dose.

Testing improved mobility

Measuring improvement is difficult in a small study, particularly in Parkinson's disease patients. Your symptoms vary and fluctuate from day to day. However, there were encouraging signs in the Phase 1 trial. A rating scale called MDS-UpDRs – developed by the International Parkinson and Movement Disorder Society – assigns a score with a 50-question assessment of motor and non-motor symptoms.

“We particularly focused on changes in motor symptoms – Part III of this scale, from medications,” says Dr. Studer. "Neurologists say that things usually get a little worse every year with this disease, meaning the score goes up by a few points. In our study, not only did the score not get worse, but it fell by more than 20 points in the high-dose group."

Another score in the study assessed how many hours in a day a patient reported being “on” (well with minimal symptoms) or “off” (problems moving and functioning normally). Even with effective medications, patients have hours every day.

“With the treatment, patients in the high-dose group gained an average of 2.7 hours per day per day, a result that could be very useful for their everyday life,” says Dr. Studer.

“There are still a lot of unknowns, but we are very happy with the results,” says Dr. Tabar. "This has been more than 20 years in the making. It is very exciting and a privilege to both develop early basic science in the laboratory and see a clinical trial. This is the type of world-class, exciting science that is possible at MSK."

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