Novel Parkinson’s Treatment Shows Promise in Case Study

Skin fibroblast-derived dopaminergic progenitor cells from a Parkinson’s disease patient that were injected into his putamina showed evidence of survival and clinical relevance.

Progenitor cell injections 6 months apart, first to the left, then to the right, putamen of a 69-year-old man showed evidence of function and survival on fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) PET and MRI, reported Jeffrey Schweitzer, MD, PhD, of Massachusetts General Hospital, and coauthors, in The New England Journal of Medicine. At 24 months after the first injection, motor scores and quality of life measures also had improved.

The patient’s four-drug Parkinson’s disease (PD) regimen at 24 months was similar to his pre-procedure treatment, which included 904 mg of levodopa equivalents daily, but with levodopa equivalents reduced to 847 mg.

“Clinical changes appeared gradually during the 18 to 24 months after implantation, a time frame consistent with gradual reinnervation of the putamen by projections from dopaminergic neurons,” Schweitzer and colleagues wrote.

“During this time, the levodopa equivalent daily dose decreased by 6%, a reduction of uncertain clinical importance,” they added. “At the dose of cells implanted, after 18 to 24 months of follow-up, we did not observe dyskinesias or other adverse neurologic effects.”

In Parkinson’s disease, dopaminergic neurons in the midbrain die. They project to higher structures in the striatum — a cluster of interconnected nuclei (cell bodies) that includes the putamen — and loss of dopaminergic signaling there gives rise to some manifestations of the disorder. Treatment largely revolves around boosting available dopamine in this area. This is done in several ways: providing remaining dopaminergic midbrain cells with the precursor to make more dopamine (levodopa), giving synthetic dopamine (agonists like pramipexole or rotigotine), or treating with agents that prolong dopamine action (like entacapone or rasagiline).

Other approaches include anticholinergic medications and amantadine, deep brain stimulation, and transplanting catecholamine-rich tissue into the dopamine-deficient area in the hope it will survive and provide physiologically meaningful dopaminergic innervation.

Past approaches to tissue transplantation have sourced tissue from the adrenal medulla and more recently, fetal midbrain, and implanted it into the striatum. The use of fetal tissue has been limited by ethical concerns, cell-product production issues, immunogenicity, and adverse effects such as graft-induced dyskinesia.

Since the authors of a 2004 review of fetal tissue transplants in PD observed that “a clinically competitive cell replacement therapy for PD will require not only the availability of large numbers of [dopaminergic] neurons, possibly generated from stem cells,” advances in generating specific cell lines differentiated toward, but not completely to, a given phenotype from induced pluripotent stem cells (iPSCs) set the stage for Schweitzer’s team to generate, inject, and evaluate such cells.

The team first performed a skin biopsy and harvested fibroblasts that were used to generate lines of iPSCs, which were then screened for pluripotent differentiation potential (i.e., lines that could differentiate into many different cell types under the right circumstances) and to eliminate potentially harmful mutations. They found an iPSC clone capable of becoming midbrain dopaminergic progenitor cells (mDAPs) and guided its differentiation into 28-day mDAPs and showed that mDAP-derived neurons secreted dopamine and had electrophysiologic properties similar to the substantia nigra dopaminergic midbrain neurons that die out in PD. The final cell product used for injection was then treated to eliminate undifferentiated iPSCs and ensure absence of serotonergic cells that may contribute to graft-induced dyskinesia.

A series of murine experiments established that the grafts were rejected in allogeneic humanized mice, while injected cells in patient-humanized mice survived and stained positively for markers of dopaminergic neurons.

“No immunosuppression was used in the course of this patient’s treatment, given the hypothesis that the autologous source of the original fibroblasts would yield an implantable cell product recognized as self,” the authors noted. “The graft-survival experiments in autologous as compared with allogeneic humanized mice reported here support this hypothesis.”

At baseline, the 69-year-old right-handed idiopathic PD patient had been taking extended release carbidopa-levodopa, rotigotine, and rasagiline and was experiencing 3 “off” hours daily. He was unable to increase levodopa due to hypotension at higher doses. At time 0 he had implantation of 4 million cells in the left putamen, and at 6 months, a similar injection on the right. The patient was discharged after overnight observation following each procedure.

Imaging using 18F-DOPA PET at 24 months showed increased uptake greater on the right (where the second injection was done at 6 months) but also present on the left, with semi-quantitative change from baseline reported as -4.0% to 13.5% (right) and -4.8% to 9.8% (left).

“Improvements in the 18F-DOPA PET signal were modest but were most prominent near the graft sites in the posterior putamen, the sub-region in which decreased uptake is typical in Parkinson’s disease,” the authors observed.

MRI at 6 months and later showed increased T2 signal intensity at the graft sites in the putamina and parts of the surgical approach trajectories.

No adverse events were reported at 24 months. At time of first injection, the patient’s PDQ-39 score, (a quality of life in PD measure with scores ranging from 0 to 156; lower is better) was 62; 24 months later it was 2.

At 4 weeks, his MDS-UPDRS part III motor assessment during “off” periods was 43; at 24 months it was 33 (scores range from 0 to 132; higher scores are worse). “On” period motor assessment values were 38 at time 0 (first injection) and 29 at 24 months.

“The improvements in motor assessments and patient-rated symptom scales in our patient should be interpreted with caution, because both he and the raters were aware of the intervention and there were no control comparisons,” Schweitzer and colleagues noted.

Studies of fetal-tissue transplantation also have suggested longer follow-up may be needed to reach definitive conclusions about graft survival, they pointed out.

“Further studies are warranted to address how this approach will perform in a variety of patients with diverse genetic backgrounds and disease phenotypes over a period longer than 24 months,” they added.

1. Skin fibroblast-derived dopaminergic progenitor cells from a Parkinson’s disease patient that were injected into his putamina showed evidence of survival and clinical relevance, and at 24 months after first injection PET and MRI imaging suggested graft survival and dopaminergic function, and quality-of-life and motor function scores improved.

2. Be aware that while this case study shows potential benefits more study is needed to determine if this therapy is generalizable to a variety of patients and disease phenotypes.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Cat ID: 37

Topic ID: 82,37,730,37,192,925