Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Abstract

Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with 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 potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cellderived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immuno suppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

Long‐term immunosuppression for CNS mouse xenotransplantation: Effects on nigrostriatal neurodegeneration and neuroprotective carotid body cell therapy

“…29,50,52,53 Different preclinical studies have analysed the effects of immunosuppression, based on CsA administration, on anti-parkinsonian cell therapy. 29,46,[54][55][56][57][58][59] However, in most of the studies using PD rodent models the period of CsA administration (1-6 weeks) is short, especially if it is compared with the slow and progressive natural course of the disease. This lack of studies that evaluate the longterm effects of immunosuppression on PD cell therapy is probably related with the adverse effects of drug treatments, 60 57 Moreover, this pattern of CsA administration produces a less accused reduction of the peripheral immunity but with a significant reduction of CD4 + T h lymphocytes which are considered the drivers of neural xenografts rejection.…”

“…29,46,[54][55][56][57][58][59] However, in most of the studies using PD rodent models the period of CsA administration (1-6 weeks) is short, especially if it is compared with the slow and progressive natural course of the disease. This lack of studies that evaluate the longterm effects of immunosuppression on PD cell therapy is probably related with the adverse effects of drug treatments, 60 57 Moreover, this pattern of CsA administration produces a less accused reduction of the peripheral immunity but with a significant reduction of CD4 + T h lymphocytes which are considered the drivers of neural xenografts rejection. [62][63][64] This "mild" immunosuppression is sufficient to preserve the neural graft survival and functionality, preventing the appearance of infections or alterations on experimental animals.…”

Inhibition of Dopamine Receptor in Neonate Hippocampus: Immunolocalization of Post Synaptic Density Protein-95 and Dopamine Receptor in vivo

“…Laoye et al, Biol Med (Aligarh) 2018, 10:3 DOI: 10.4172/0974-8369.1000441 [6]. Studies have shown that antipsychotics such as Haloperidol which causes dopamine receptor blockade may lead to Parkinsonism and progressively lead to Schizophrenia [7].…”

Bringing Neural Cell Therapies to the Clinic: Past and Future Strategies

“…Homozygous cells have fewer human leukocyte antigen (HLA) alleles, reducing the immunogenicity of transplanted cells. The cell product called ISC-hpNSCs is directed to a “generic” (presumably forebrain fated) neural stem cell 39, 40. ISCO has entered a phase 1 trial for PD in Australia and recently reported transplanting their first patient 41 .…”