Cell Transplantation and Gene Therapy in Parkinson's Disease

Abstract

Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate.

Neural Fate of Mesenchymal Stem Cells and Neural Crest Stem Cells: Which Ways to Get Neurons for Cell Therapy Purpose?

“…One of the main goals in this field relies in the replacement of lost dopaminergic neurons in the nigrostriatal system, which could be achieved through the use of different types of stem cells. As explained earlier, MSCs/NCSCs are interesting candidates in this objective [115].…”

1980-2011: Parkinson's Disease and Advance in Stem Cell Research

“…Grafting of engineered SCs in this case provides a substantial reservoir allowing the unlimited supply of the required substance without the requirement of invasive injection pumps, as detailed below. Several SC types have already been transplanted in PD animal models yielding interesting but variable results (Wakeman et al, 2011). SCs can be efficiently derived from early stage embryos (pluripotent SCs with unlimited potential to differentiate) or from committed resident tissues (multipotent SCs with restricted potential to differentiate).…”

“…However, although efficacy of this approach has now been asserted in numerous pre-clinical studies utilizing animal models of PD, positive outcomes in clinical trials involving PD patients have been very variable and rather modest, and have been plagued by graft-induced dyskinesias. New sources for cell replacement and particularly stem cells (including induced patient-derived cells) may now provide advantages for future clinical therapies (Wakeman et al, 2011). This chapter will briefly introduce rodent and nonhuman primate PD-like models commonly used in pre-clinical studies, which represent a fundamental platform for the preclinical evaluation of innovative interventions.…”

Noninvasive near-infrared live imaging of human adult mesenchymal stem cells transplanted in a rodent model of Parkinson’s disease

“…Thus, considerable progress lies ahead to reach substantial and detectable therapeutic effects. 3 Many regulatory pathways and environmental factors may govern stem cell behavior following transplantation in patients with Parkinson's disease. 4 The development of effective cell-based therapies to treat neurodegeneration therefore requires an extensive comprehension of the progressive environmental cues and reciprocal interactions between the host and donor cells.…”