A Step Towards Restorative Therapy in Parkinson's Disease

Abstract & Commentary

By Claire Henchcliffe, MD Dr. Henchcliff is Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.

Synopsis: Dopamine neuronal replacement cell therapy can be beneficial for patients with advanced disease, and that changing technical approaches could have a favorable impact on efficacy and adverse events following neural transplantation.

Source: Mendez I, et al. Cell Type Analysis of Functional Fetal Dopamine Cell Suspension Transplants in the Striatum and Substantia Nigra of Patients with Parkinson's Disease. Brain. 2005;128;1498-1510.

The present study describes autopsy findings in 2 patients with advanced Parkinson's disease (PD), who received bilateral cell suspension transplants (CST) derived from fetal ventral midbrain tissue. Patients 1 and 2 were 69 and 59 years old with PD for 15 and 11 years, respectively. Both had severe motor fluctuations and dyskinesias (50% off time for each; Unified Parkinson's Disease Rating Scale (UPDRS) motor scores 50 and 84 off, 30 and 42 on, dyskinesia scores 12 and 23, respectively). Tissue was obtained in Halifax, Canada, from elective pregnancy terminations at 6-9 weeks, a stage prior to establishment of dopaminergic projections to the striatum. Fetal ventral midbrains were isolated and, after exposure to GDNF, cells were mechanically dissociated. Surgery was a 2-stage procedure. Using stereotactic localization and injecting through a customized cannula, between 5.0 x 105 and 4.8 x 106, cells were transplanted along 4 tracks into the postcommissural putamen bilaterally, and in patient 2, also along 2 tracks, oriented from caudate to putamen. Patient 2 additionally received transplantation to the dorsal rostral substantia nigra (SN).

No symptomatic procedure-related complications occurred, but bleeding through the cannula prevented completion of CST on the left for patient 2. Cyclosporine was given 2 weeks prior to and 6 months after CST. Both patients improved clinically after CST, as measured by UPDRS scores, with reduction of total off-time from 50% to 25% at 3 years, a 34% and 84% improvement in dyskinesia score for patients 1 and 2, respectively, and improved motor scores on and off. In patient 2, despite marked improvement on the left, symptoms worsened on the right. [18]F- fluorodopa PET scans demonstrated between 90% and 306% increased uptake in the striatum at 2.7 and 3 years after CST. Patient 1 died 44 months after transplant and patient 2 died at 52 months after transplant, from unrelated causes.

At autopsy, the number of striatal dopaminergic cells (reflected by tyrosine hydroxylase positive (TH+) immunoreactivity) corresponded to 15-30% of transplanted dopaminergic cells, and innervated the surrounding striatum. In patient 2, surviving cells were absent on the left side. Only 4-8% of cells survived in the midbrain grafts. Subtyping of grafted TH+ striatal cells revealed that 68-71% expressed the K+ channel protein, Girk2, found in the ventral tier of dopaminergic neurons of the SN pars compacta in normal tissue. Only 26-48% of grafted TH+ cells expressed calbindin, present in dopaminergic neurons of the ventral tegmental area and lateral SN. There was no inflammatory response around surviving cells, but activated microglia and macrophages only along needle tracks.

Commentary

Mendez and colleagues present the first autopsy report of patients receiving fetal ventral midbrain CST for PD. In this study, the 2 patients had significant clinical improvement, as well as a functional imaging response corresponding to surviving grafted dopaminergic neurons. The unfortunate failure of CST in the left putamen of patient 2 served as negative control, as this patient's PD symptoms progressed on the right. Previous studies used solid tissue from fetal midbrain, and there are a number of significant differences in outcomes.1, 2 Solid tissue transplant recipients have suffered from highly debilitating off dyskinesias. In contrast, both patients reported here experienced reduction in frequency and severity of levodopa-induced dyskinesias, and off dyskinesias were absent.

The difference in outcomes raises many questions, largely because of lack of standardization of cell transplant protocols from center to center. First, the role of immunosuppression has been much debated: in this study. Despite cyclosporine administration for only 6 months, graft survival was significant at autopsy, and there was no significant inflammatory response at the graft sites. This contrasts with inflammatory reactions observed around the cases of solid fetal midbrain transplant recipients who have come to autopsy. Second, the way in which tissues are treated prior to transplantation varies: Mendez et al exposed cells to GDNF, which has diverse positive effects on dopaminergic cell survival and function. Third, and importantly, Mendez et al address the thorny issue of patterns of re-innervation. If cell transplants are to function optimally, then dopamine needs to be appropriately delivered. Girk2+ TH+ neurons of the ventral SN pars compacta innervate mostly the posterior part of the putamen, and are the prevalent degenerating neurons in PD.

Dopaminergic re-innervation of this striatal compartment is thought to be necessary for alleviation of motor symptoms in PD. Many transplanted fetal neurons indeed differentiated to Girk2+ TH+ neurons, resembling native dopaminergic SN pars compacta neurons. Moreover, they re-innervated the posterior putamen. Despite small numbers of patients, these results are encouraging and, based on findings in this paper, focusing on isolation and expansion of dopaminergic neurons that differentiate to Girk2+ TH+ neurons for CST may be a promising strategy for restorative therapy in PD.

References

1. Freed CR, et al. Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease. N Engl J Med. 2001;344:710-719.

2. Olanow CW, et al. A Double-Blind Controlled Trial of Bilateral Fetal Nigral Transplantation in Parkinson's Disease. Ann Neurol. 2003;54:403-414.