A novel treatment that reprogrammed the skin cells of a single patient with Parkinson disease (PD) to replace cells in the brain improved symptoms over 24 months, according to a study published Wednesday, although researchers cautioned that a longer, more diverse clinical trial is needed to demonstrate results.
A novel treatment reprogrammed the skin cells of a single patient with Parkinson disease (PD) to replace damaged brain cells, according to study findings published today in The New England Journal of Medicine. But researchers cautioned that larger clinical studies are needed to demonstrate long-term results.
Since the 1980s, researchers have studied the potential of tissue transplantation in patients with PD (PwP) to replace the dopaminergic neurons lost from the disease. However, inconsistent improvement in symptoms has been noted in prior approaches using fetal cell—based therapies, including graft-induced dyskinesias and issues of immunosuppresion, as well as government restrictions on research.
Researchers highlight that recent advances in the technology for creating induced pluripotent stem cells (iPSCs), derived from the midbrain dopaminergic progenitor, offer the potential of achieving the benefits of fetal-tissue transplantation without those concerns.
“Current drugs and surgical treatments for Parkinson disease are intended to address symptoms that result from the loss of dopaminergic neurons, but our strategy attempts to go further by directly replacing those neurons,” said senior author Kwang Soo Kim, PhD, director of the Molecular Neurobiology Laboratory at McLean Hospital.
Researchers from McLean Hospital and Massachusetts General Hospital (MGH) reprogrammed the skin cells of a 69-year-old man with a 10-year history of progressive idiopathic PD to the embryo-like iPSCs and subsequently differentiated them to take on the characteristics of dopaminergic neurons.
Because the man contributed funding to the team's research, "the team extensively consulted with the MGH Institutional Review Board to discuss how to conduct this work ethically," according to the statement. The study was also supported by the National Institutes of Health, the Parkinson’s Cell Therapy Research Fund at McLean Hospital and MGH, and the William and Elizabeth Sweet Endowed Professorship in Neuroscience at Harvard Medical School.
After applying for and gaining approval under the FDA’s single-patient, expanded-access protocol, Kim then implanted the replacement dopamine neurons into the patient’s brain in 2 surgeries, 1 each in 2017 and 2018, at Weill Cornell Medical Center and MGH. Four million cells were delivered at each surgery.
Before the treatment, the patient's medication involved extended-release carbidopa—levodopa (23.75 mg and 95 mg, respectively, at a dosage of 3 capsules 4 times daily), rotigotine (4 mg daily), and rasagiline (1 mg daily). The total daily dose was 904 mg of levodopa equivalents. His symptoms included 3 hours of “off” time per day, characterized by worsening tremor, posture, and fine motor control. Increasing the levodopa dose caused orthostatic hypotension. He did not have dyskinesias.
Imaging tests after a 2-year follow-up revealed that the transplanted cells are functioning as dopaminergic neurons and immunosuppresants are not required. In addition, the patient reported less than 1 hour of “off” time per day, and the dose of his levodopa equivalents fell by 6%. His medication included extended-release carbidopa—levodopa (23.75 mg and 95 mg, respectively, at a dose of 3, 3, 2, and 3 capsules 4 times daily), rotigotine (4 mg daily), rasagiline (1 mg daily), and droxidopa (100 mg daily). The total daily dose was 847 mg of levodopa equivalents.
“Because the cells come from the patient, they are readily available and can be reprogrammed in such a way that they are not rejected on implantation. This represents a milestone in ‘personalized medicine’ for PD,” said Kim.
Since the surgery, the patient has noted improvements in day-to-day activities requiring motor skills, as well as quality of life, although the authors noted that the improvements should be viewed with caution since the intervention was not blinded and there was no control.
Lead author Jeffrey Schweitzer, MD, PhD, a PD-specialized neurosurgeon and director of the Neurosurgical Neurodegenerative Cell Therapy program at MGH, noted that the results represent 1 patient’s experience and that a formalized clinical trial is warranted to show whether more PwP could expect similar improvements. “With that said, the outcome is extremely encouraging for the future prospects of this technique,” said Schweitzer.
Schweitzer JS, Song B, Herrington TM, et al. Personalized iPSC-Derived dopamine progenitor cells for Parkinson’s disease [published online May 13, 2020]. N Engl J Med. doi:10.1056/NEJMoa1915872