Patient-derived iPSC modeling of rare neurodevelopmental disorders: Molecular pathophysiology and prospective therapies

Neurosci Biobehav Rev. 2021 Feb:121:201-219. doi: 10.1016/j.neubiorev.2020.12.025. Epub 2020 Dec 25.


The pathological alterations that manifest during the early embryonic development due to inherited and acquired factors trigger various neurodevelopmental disorders (NDDs). Besides major NDDs, there are several rare NDDs, exhibiting specific characteristics and varying levels of severity triggered due to genetic and epigenetic anomalies. The rarity of subjects, paucity of neural tissues for detailed analysis, and the unavailability of disease-specific animal models have hampered detailed comprehension of rare NDDs, imposing heightened challenge to the medical and scientific community until a decade ago. The generation of functional neurons and glia through directed differentiation protocols for patient-derived iPSCs, CRISPR/Cas9 technology, and 3D brain organoid models have provided an excellent opportunity and vibrant resource for decoding the etiology of brain development for rare NDDs caused due to monogenic as well as polygenic disorders. The present review identifies cellular and molecular phenotypes demonstrated from patient-derived iPSCs and possible therapeutic opportunities identified for these disorders. New insights to reinforce the existing knowledge of the pathophysiology of these disorders and prospective therapeutic applications are discussed.

Keywords: 3D brain organoids; Alexander disease; Angelman syndrome; CRISR/Cas9 technology; Directed differentiation; Dravet syndrome; Fragile X syndrome; Friedreich’s ataxia; Huntington’s disease; Induced pluripotent stem cells; Miller dieker syndrome; Phelan-McDermid syndrome; Rare neurodevelopmental disorders; Rett syndrome; Spinal muscular atrophy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Differentiation
  • Humans
  • Induced Pluripotent Stem Cells*
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / therapy
  • Neurons
  • Prospective Studies