By Emily Leclerc, Waisman Science Writer
When Su-Chun Zhang, MD, PhD, picked up the phone to answer a call in 2001, he could barely understand the man speaking on the other line. “I could not hear his voice clearly,” says Zhang, a Waisman investigator and professor of neuroscience and neurology. It turns out that the man, who was calling from Texas, was on a ventilator which was garbling his voice. “He had ALS,” Zhang recalls. Amyotrophic lateral sclerosis (ALS), is a devastating and progressive neurodegenerative disease that causes the degeneration of motor neurons, a specific type of nerve cell in the brain and spinal cord, leading to eventual paralysis and death.
The man was calling in response to one of Zhang’s scientific papers on coaxing embryonic stems cells into becoming neuronal stem cells. The Texan implored Zhang to focus his work more specifically on motor neurons. “I said I had never worked on motor neurons. He said you need to work on it. You need to do this,” Zhang says. Little did Zhang know then that this phone call would change the course of his research and lead to a potential treatment not only for ALS, but also for Parkinson’s disease.
In 2001, Zhang became the first in the world to generate neurons from human embryonic stem cells. This ground-breaking discovery opened countless doors, including the path toward differentiating stem cells into all different kinds of neurons. By 2005, his lab succeeded in generating motor neurons from human stem cells, for the first time in the world. If stem cells could become motor neurons, why not GABAergic neurons or dopaminergic neurons? With that discovery, Zhang began looking at the possibility of using stem cells to replace damaged or deteriorating neurons with healthy ones as a potential treatment for conditions like ALS and Parkinson’s disease.
The gradual degeneration of dopaminergic neurons in the brain causes the uncontrollable movements that are often associated with Parkinson’s that worsen over time. The condition can be debilitating, leaving individuals unable to walk, dress, and even feed themselves. The current treatments deal with some of the symptoms but do not stop the degeneration of dopaminergic neurons, hence the therapies losing efficacy after several years.
Zhang questioned whether those deteriorating neurons could be replaced with healthy transplanted neurons. The idea is that healthy dopaminergic neurons could be grown from stem cells and then transplanted into the patient’s brain to replace the damaged ones. If proven possible, a patient could, at the very least, have milder symptoms and at the most, be cured. With this moonshot in mind, Zhang started on the path that has driven much of his career for the last two decades.
The foundation of this stem cell treatment for Parkinson’s has proven possible in animal models. Zhang successfully transplanted healthy iPSC stem cell-derived dopaminergic neurons into the brains of mice and monkeys with Parkinson’s, with both species seeing remarkable reductions in symptoms. Studies led by Zhang have also continued to show that, in mouse and monkey models, the new neurons integrate well into the brain and help to restore damaged circuitry.
In 2023, Zhang and his company BrainXell (pronounced brain cell) are closer than ever to human clinical trials for the transplanted stem cell therapeutic. The studies in mice and monkeys have shown that the transplanted dopaminergic cells find their way in the brain and connect to the right targets. In the animal models, the cells were found to be safe and effective over a long period of time and showed consistent recovery of disease symptoms. The next step is to procure Food and Drug Administration (FDA) approval to begin the human clinical trial. Already in the midst of that process, Zhang is hopeful they will receive approval in the near future.
Many of the components of the clinical trial are already in place. Once approved and with additional funding secured, the clinical trial will seek study participants in consultation with neurologists and neurosurgeons. Individuals will not be able to self-refer to participate in the study. Selected study participants will provide a blood or skin sample that will be converted to iPSCs. Zhang has created new technology that streamlines the process of guiding stem cells to neurons that makes the cells safer and more effective. The dopaminergic cells will then be transplanted into the study participants who will then be followed over an extended time period. If successful, the trial would move on to additional trial phases, which can be long and arduous, before being considered for FDA approval.
“This is probably one of the most exciting events in my career because, out of medical school, I wanted my research to be related to clinical application,” Zhang says. “I told myself a long time ago that my goal is to at least try and get one thing to patients, ideally before my retirement.” And now, that goal is only steps away from becoming a reality.