Proof of Concept Studies Exploring the Safety and Functional Activity of Human Parthenogenetic-Derived Neural Stem Cells for the Treatment of Parkinson's Disease

Abstract

Recent studies indicate that human pluripotent stem cell (PSC)-based therapies hold great promise in Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying viable human embryos and can be used to generate an unlimited supply of neural stem cells for transplantation. Here we evaluate for the first time the safety and engraftment of human parthenogenetic stem cell-derived neural stem cells (hpNSCs) in two animal models: 6-hydroxydopamine (6-OHDA)-lesioned rodents and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates (NHPs). In both rodents and nonhuman primates, we observed successful engraftment and higher dopamine levels in hpNSC-transplanted animals compared to vehicle control animals, without any adverse events. These results indicate that hpNSCs are safe, well tolerated, and could potentially be a source for cell-based therapies in PD.

The role of cell based therapy in the treatment of Parkinson’s disease

“…This technique reduced the dosage requirement of anti-PD drugs. Additionally, they improve the motor signs of PD [18][19][20][21]. Some of the early studies found that the formation of tumor after embryonic stem cell transplantation is a major drawback of this technique [22,23].…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…First clinical trials (Lindvall et al, 1988) were again initially promising (Lindvall et al, 1990) but were later held back due to efficiency concerns following studies with a larger number of patients and randomized, double-blind, placebo-controlled protocols (Freed et al, 2001;Olanow et al, 2003) that showed no significant difference between grafted patients and placebo, with several patients developing graft-induced dyskinesia. Nevertheless, retrospective analyses and reports on those clinical trials of fVM striatal grafts demonstrated their efficiency either clinically (Kefalopoulou et al, 2014), histologically (Li et al, 2016), behaviorally (Gordon et al, 2004) or functionally (Politis and Piccini, 2010). Based on all these evidences, a new clinical trial of fVM transplantation has been started on a cohort of patients with improved grafting procedures and selection of patients (Moore et al, 2014) with the aim of preparing for the move to stem-cell-based transplantation in humans while waiting for preclinical investigation reports in animal models.…”

“…Human ESCs (Kriks et al, 2011;Daadi et al, 2012;Doi et al, 2012;Grealish et al, 2014;Gonzalez et al, 2015Gonzalez et al, , 2016Chen et al, 2016) and monkey ESCs (Kawasaki et al, 2002;Sanchez-Pernaute et al, 2005;Takagi et al, 2005;Xi et al, 2012) were first used, recently followed by human iPSCs (Kikuchi et al, 2011;Kriks et al, 2011;Sundberg et al, 2013;Doi et al, 2014) and monkey iPSCs (Morizane et al, 2013;Sundberg et al, 2013;Wang et al, 2015).…”

“…They express the stem cell markers NESTIN, SOX2, VIMENTIN and MUSASHI; are karyotypically normal; and can be amplified for long periods of time in culture without losing their properties (Redmond Jr. et al, 2007;Bjugstad et al, 2008;Wakeman et al, 2014;Gonzalez et al, 2015. Following testing for various contaminants (virus, mycoplasma, bacteria, etc.…”

“…Following testing for various contaminants (virus, mycoplasma, bacteria, etc. ), they constitute working cell banks prepared under GMP-grade conditions (Gonzalez et al, 2015. NSC lines can further be carefully preselected for transplantation on the basis of their capacity to differentiate into DA progenitors in response to DA induction in vitro and to give rise to various neuronal and glial cell types upon transplantation into different regions of the mouse brain in vivo (Redmond Jr. et al, 2007).…”