Stem cell therapy for Parkinson’s disease: safety and modeling

Abstract

For decades, clinicians have developed medications and therapies to alleviate the symptoms of Parkinson’s disease, but no treatment currently can slow or even stop the progression of this localized neurodegeneration. Fortunately, sparked by the genetic revolution, stem cell reprogramming research and the advancing capabilities of personalization in medicine enable forward-thinking to unprecedented patient-specific modeling and cell therapies for Parkinson’s disease using induced pluripotent stem cells (iPSCs). In addition to modeling Parkinson’s disease more accurately than chemically-induced animal models, patient-specific stem cell lines can be created, elucidating the effects of genetic susceptibility and sub-populations’ differing responses to in vitro treatments. Sourcing cell therapy with iPSC lines provides ethical advantages because these stem cell lines do not require the sacrifice of human zygotes and genetically-specific drug trails can be tested in vitro without lasting damage to patients. In hopes of finally slowing the progression of Parkinson’s disease or re-establishing function, iPSC lines can ultimately be corrected with gene therapy and used as cell sources for neural transplantation for Parkinson’s disease. With relatively localized neural degeneration, similar to spinal column injury, Parkinson’s disease presents a better candidacy for cell therapy when compared to other diffuse degeneration found in Alzheimer’s or Huntington’s Disease. Neurosurgical implantation of pluripotent cells poses the risk of an innate immune response and tumorigenesis. Precautions, therefore, must be taken to ensure cell line quality before transplantation. While cell quality can be quantified using a number of assays, a yielding a high percentage of therapeutically relevant dopaminergic neurons, minimal de novo genetic mutations, and standard chromosomal structure is of the utmost importance. Current techniques focus on iPSCs because they can be matched with donors using human leukocyte antigens, thereby reducing the severity and risk of immune rejection. In August of 2018, researchers in Kyoto, Japan embarked on the first human clinical trial using iPSC cell therapy transplantation for patients with moderate Parkinson’s disease. Transplantation of many cell sources has already proven to reduce Parkinson’s disease symptoms in mouse and primate models. Here we discuss the history and implications for cell therapy for Parkinson’s disease, as well as the necessary safety standards needed for using iPSC transplantation to slow or halt the progression of Parkinson’s disease.

Enhanced differentiation of human induced pluripotent stem cells toward the midbrain dopaminergic neuron lineage through GLYPICAN-4 downregulation

“…In vivo, hPSC‐derived VMDA neurons are considered potential therapeutics for PD treatment. Outcomes from preclinical studies showing that hPSCs‐derived VMDA progenitors engrafted in the striatum of rat or monkey PD models survive, integrate into the host structure, and provide functional recovery 12,13 have now set the basis for the first clinical trials in PD patients 14,15 . In view of these promising therapeutic perspectives for PD, intense research efforts are focused on defining strategies to optimize generation of authentic and functional VMDA neurons for in vitro and in vivo applications.…”

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

“…SCs-based therapies are widely used in the treatment of various diseases[ 14 - 18 ]. Limbal stem cell therapy is used for treating burn-related corneal destruction[ 19 ], NSCs in gastrointestinal tract disorders[ 20 ], bone marrow-derived mesenchymal SCs (BM-MSCs) in diabetic cardiomyopathy[ 21 ], and MSCs in multiple sclerosis[ 22 ] and several clinical conditions.…”

Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation

“…Here, we develop and apply a multiplexing strategy to profile the differentiation and maturation of more than two hundred iPSC lines derived from the Human Induced Pluripotent Stem Cell Initiative (HipSci) towards a midbrain neural fate, including dopaminergic neurons (DA). DA are involved in motor function and other cognitive processes and play key roles in neurological disorders, including Parkinson's Disease 10,11 (PD ). To study how these cells differentiate, and how genetic background could influence differentiation, we employed a well-established protocol 12 and collected cells at three maturation stages (progenitor-like, young neurons, and more mature neurons), covering 52 days of differentiation.…”