A stem cell–based therapy initially developed at Memorial Sloan Kettering Cancer Center (MSK) may lead to a new treatment for advanced Parkinson's disease, according to results from a phase 1 clinical trial reported in 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 unusually low levels of dopamine, and as a result suffer from tremors, slowness, stiffness, and walking or balance problems.
The 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 trial is a two- year study sponsored and conducted by BlueRock at multiple centers within the US and Canada. One of the principle 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 taken hold in the brain with no serious side effects. Notably, some patients appeared to have stabilization or an improvement in their Parkinson's-related symptoms.
Based on these preliminary results, the U.S. Food and Drug Administration (FDA) has given approval to proceed directly to a phase 3 clinical trial in a much larger patient group. That trial is expected to start in the first half of 2025.
"This is an important milestone on the road towards regenerative brain repair," says Dr. Tabar, who helped lead the clinical trial and is the study's first author. "It represents more than two decades of collaborative work, based on very rigorous science beginning in our labs. It might seem unusual for a cancer center to pursue regenerative medicine for a neurodegenerative disease, but if we can figure out how to replenish cells lost to disease in the brain and rebuild circuitry, we can extend it to other treatments, and eventually cancer patients will benefit."
Turning Stem Cells Into Neurons
The researchers created a method for coaxing 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 bemdaneprocel, can be frozen until ready for use.
"This is a big step for the stem cell field — to see these encouraging results from a truly off-the-shelf dopamine neuron product in patients with Parkinson's disease," Dr. Studer says. "We are excited to see this move forward into a larger, randomized trial."
The researchers note that the phase 1 trial involved a small patient group and had no control arm. The upcoming phase 3 trial, which will include around 100 people, is expected to produce more definitive results, because one group of patients will receive a placebo treatment. Also, the phase 1 patients will continue to be evaluated to determine if the therapy has lasting effects beyond the two years of this study period.
The phase 3 trial is being sponsored and conducted by BlueRock Therapeutics, where Drs. Studer and Tabar are scientific co-founders.
MSK's History of Stem Cell Research for Parkinson's
The phase 3 trial is the culmination of research going back 25 years, when Dr. Studer first came to MSK and began investigating embryonic stem cells as a potential treatment for various diseases. His lab has collaborated with Dr. Tabar's lab over the past two decades with a particular focus on applying 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, with symptoms slowly worsening over time. It affects nearly 1 million people in the U.S. and more than 6 million people worldwide.
In the past 50 years, progress in 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 seen as 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.
Beginning in 2009, researchers in the Tabar and Studer labs made a series of discoveries using embryonic stem cells, which are pluripotent, meaning they can develop into any cell type. The teams found these pluripotent cells could be reliably directed to turn into dopamine neuron progenitors. They continued refining their methods to ensure purity and quality control and conducted repeated tests in animal models.
"For the initial study, we could produce the progenitor cells here at the MSK facility under clinical-grade conditions, without any dependence on an outside source," Dr. Studer says. "This lets us create a very large number of cells that are ready for use."
In 2021, they published two definitive papers in the journal Cell Stem Cell showing the safety and effectiveness of bemdaneprocel in animals. This led to the approval of the phase 1 trial, which opened that year.
Efforts to Prevent Side Effects
In the trial, nine patients were transplanted at MSK, and three were transplanted by collaborators in Toronto. The embryonic stem cells come from a donor, so patients receiving the dopamine-producing neurons received one year of immune-suppressing drugs so they would not reject the transplant.
Past trials using fetal tissue as a source of dopamine neurons had problematic side effects — mainly involuntary movement called graft-induced dyskinesia. But the MSK researchers appear to have solved this issue.
"We were naturally concerned about dyskinesia and looked very carefully for it in our trial," Dr. Studer says. "One of the very gratifying results was that we didn't see any evidence with our treatment. Overall, there were no serious side effects from the transplanted cells or immunosuppression."
An important tool for making the implantation safe was MSK's intraoperative MRI capabilities, which provide live imaging during the procedure. "It enabled us to deliver the cells exactly where they are needed with the lowest possible risk," Dr. Tabar says.
Two different doses of the dopamine-producing cells were tested in the clinical trial. Both levels appeared safe, but the higher dose seemed more effective at 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, especially in Parkinson's patients. Their symptoms vary and fluctuate day to day. But there were encouraging signs in the phase 1 trial. A ratings scale called MDS-UPDRS — developed by the International Parkinson and Movement Disorder Society — assigns a score using a 50-question assessment of motor and nonmotor symptoms.
"We were particularly focused on changes in the motor symptoms scores — part III of this scale, off medications," Dr. Studer says. "Neurologists say things usually get a little bit 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, it dropped 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" (functioning well with minimal symptoms) or "OFF" (problems moving and functioning normally). Even with effective medications, patients have OFF hours every day.
"With the treatment, patients in the high-dose group gained an average of 2.7 hours of ON time per day, a result that could be quite meaningful for their everyday life," Dr. Studer says.
"There are still a lot of unknowns, but we are very pleased with the results," Dr. Tabar says. "This was more than 20 years in the making. It is very exciting and a privilege to be able to develop both the early basic science in the lab and see it all the way through to a clinical trial. This is the kind of top-of-the-line, exciting science that's possible at MSK."
Funding and Disclosures
This study was sponsored by BlueRock Therapeutics. The sponsor collaborated with investigators on trial design and data collection, analysis, and interpretation. The initial work to develop bemdaneprocel (MSK-DA01) was supported by NYSTEM grant C028503 and MSK Core Grant P30 CA008748. Under the direction of the authors, Benjamin M. Hiller, PhD, of Peloton Advantage LLC, an OPEN Health company, provided medical writing support, which was funded by BlueRock Therapeutics
Dr. Tabar is a scientific adviser and receives research support from BlueRock Therapeutics. Dr. Sarva has done consulting work for Novo Nordisk, BlueRock Therapeutics, Neurocrine, and Neuroderm. She has also received clinical trial support from BlueRock Therapeutics, Prevail Therapeutics, Neuroderm, Sun Pharma, Meira GTX, Bukwang, Insightec, Biogen, Genentech, Cerevance, UCB, and National Institutes of Health (NIH).
Dr. Studer is a scientific adviser and receives research support from BlueRock Therapeutics and is a scientific co-founder of DaCapo Brainscience.
