Background & Objective: Despite the great effort spent over recent decades to unravel the
pathological mechanisms underpinning the development of central nervous system disorders, most of
them still remain unclear. In particular, the study of rare CNS diseases is hampered by the lack of postmortem
samples and of reliable epidemiological studies, thus the setting of in vitro modeling systems
appears essential to dissect the puzzle of genetic and environmental alterations affecting neural cells
viability and functionality. The isolation and expansion in vitro of embryonic (ESC) and fetal neural
stem cells (NSC) from human tissue have allowed the modeling of several neurological diseases “in a
dish” and have also provided a novel platform to test potential therapeutic strategies in a pre-clinical
setting. In recent years, the development of induced pluripotent stem cell (iPS) technology has added
enormous value to the aforementioned approach, thanks to their capability for generating diseaserelevant
cell phenotypes in vitro and to their perspective use in autologous transplantation. However,
while the potentiality of ESC, NSC and iPS has been widely sponsored, the pitfalls related to the
available protocols for differentiation and the heterogeneity of lines deriving from different individuals
have been poorly discussed. Here we present pro and contra of using ESC, NSC or iPS for modeling
rare diseases like Lysosomal Storage disorders and Motor Neuron Diseases.
Conclusion: In this view, the advent of gene editing technologies is a unique opportunity to standardize
the data analysis in preclinical studies and to tailor clinical protocols for stem cell-mediated therapy.
Keywords: Disease modeling, Stem Cells, Embryonic stem cells, Induced pluripotent cells, Neural stem cells, neurological
disorders, rare CNS diseases, Motor Neuron Diseases, Lysosomal Storage Diseases, Huntington’s Disease, Parkinson’s Disease,
Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Central Nervous System, Spinal Cord, Sub-granular Zone, Sub-
Ventricular zone, Glycosaminoglycans, Mucopolysaccharidosis, Mucopolysaccharidosis Type II or Huner Syndrome, Iduronate
2-Sulfatase, Enzyme Replacement Therapy.
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