Current treatments for Parkinson’s disease (PD) alleviate symptoms, but lead to involuntary muscle spasms and do not prevent the loss of neurons that underlie the disease. Transplanting stem cells from fetal tissue has shown enough promise to warrant clinical trials, but the approach is ethically complex and the outcomes are inconsistent, likely because of differences between donor tissues.
In a recent study published in Nature Medicine, researchers reported that transplanting personalized induced pluripotent stem cells (iPSCs) into the brains of rhesus monkeys modeling PD not only improved motor function and neuron growth over a two-year period, but also boosted the animals’ moods.1
The findings indicate clinical potential for using stem cells derived from the patient, known as autologous stem cell therapy, to treat PD. This study is the culmination of University of Wisconsin neuroscientist Su-Chun Zhang’s career-long goal to repair damaged or lost function in the brain.
“This work confirms the long-term efficacy of an autologous approach in a non-human primate model,” said Penny Hallett, co-director of the Neuroregeneration Research Institute and psychiatrist at Harvard Medical School in Belmont, Massachusetts. Hallett was not part of the new research, but her work helped to lay the foundation. In a 2015 study published in Cell Stem Cell, she and her team provided the first proof-of-concept data for an autologous iPSC approach for PD treatment in a non-human primate model.2
To find out whether transplanting iPSCs derived from an individual’s own cells would benefit parkinsonian monkeys, Zhang and colleagues generated five iPSC lines from skin cells from each of five monkeys and differentiated them into dopamine neural progenitors for autologous transplantation. They used a sixth iPSC line from a donor monkey for transplantation into five additional primates.
To replicate the onset of PD in humans, the researchers injected ten adult monkeys with a neurotoxin known as MPTP to produce Parkinson-like symptoms in the animals on one side of the body. All of the monkeys developed slow movements, postural and gait imbalances, tremors, and impaired coordination in the hand on the opposite side of the injection. Scans revealed that on the injected side, monkeys lost most brain activity involving dopamine in two key brain areas.
To best model PD, the researchers waited three years after injecting the neurotoxin to transplant the iPSCs, during which time the monkeys’ symptoms persisted. After transplanting the cells, the researchers monitored the animals for the next two years.
Zhang and his team saw that parkinsonian monkeys transplanted with autologous cells recovered. These animals moved more, moved faster, and were nimbler than before the transplant. They gained the ability to grasp treats, use all four limbs for walking, and climb their cages with ease and increased agility. In contrast, animals that received allogeneic cells, iPSCs derived from a donor, did not recover. Their symptoms remained unchanged or worsened compared to before transplantation.
This was unsurprising to Hallett, as none of the animals received immunosuppression treatment. In the clinic in humans, the allogenic approach requires immune suppression. Most patients with Parkinson’s disease are older than 60, and the risks of giving long-term immune suppression to those patients is greater as the immune system becomes less robust with age. The results support using the autologous approach over the allogeneic one, Hallett said.
After living with Parkinson symptoms for several years, many of the animals showed signs of depression. They walked nonstop around the cage, a sign of anxiety, or wouldn’t move at all, even to get treats such as marshmallows, indicating a lack of motivation. However, in monkeys that received autologous stem cell therapy, these behaviors began to subside about six months after the transplant.
The results have haunted Marina Emborg, a medical physicist at the University of Wisconsin who co-led the work with Zhang. She wants to find out why the transplanted cells helped change the animals’ moods.
Although the depressive behaviors persisted in the allogeneic but not autologous transplanted animals, Hallett is curious how non-transplanted animals would have behaved. “It’s likely that these transplants can have positive effects on other non-motor behaviors,” she said, adding that there’s anecdotal evidence for this from fetal transplantations, but she’d like more proof and to know why.
For Emborg, the answer may be as simple as regaining the ability to move. “I personally feel that if you feel better because you’re moving better also, that helps with depression,” she said.
The momentum for autologous iPSC transplant for treating Parkinson’s disease is gaining traction. Several groups, including Zhang’s and Hallett’s, are working to move the technique into small clinical trials. These ambitions follow a successful first-in-human use of the autologous approach reported last May in The New England Journal of Medicine.3
Researchers led by Kwang-Soo Kim, director of the Molecular Neurobiology Laboratory and neurobiologist at McLean Hospital in Belmont, Massachusetts, transplanted differentiated iPSCs harvested from a skin biopsy into the brain of a 69-year-old man with idiopathic PD.
Before the transplant, the patient indicated that he had worsening tremors and fine motor control. But over the two years after the autologous cell transplant, he reported no adverse effects or decline in function, and he was able to decrease the amount of daily medication he needed to control his symptoms. Scans showed that his brain was able to take up about 15 to 20 percent more dopa, a precursor of dopamine, than before the transplant. He also did not require any immunosuppression.
For Zhang, the results make it clear that autologous transplantation is the way to go. “I initially wanted to do allogeneic transplants in patients because the autologous approach is too expensive,” he said. “However, after seeing [our] data, I changed my mind. I want to go with the autologous first… because I feel the chance of success is really, really high.”
- Y. Tao et al., “Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys,” Nat Med, 27(4):632-39, 2021.
- P.J. Hallett et al., “Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease,” Cell Stem Cell, 16(3):269-74, 2015.
- J.S. Schweitzer et al., “Personalized iPSC-derived dopamine progenitor cells for Parkinson’s disease,” NEJM, 382:20, 2020.