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Creating a New Huntington's Disease Model with Direct Reprogramming

Review of "Directly reprogrammed Huntington's disease neural precursor cells generate striatal neurons exhibiting aggregates and impaired neuronal maturation" from STEM CELLS by Stuart P. Atkinson

Researchers led by Bronwen Connor (University of Auckland, New Zealand) reported the first direct generation of induced neural progenitor cells (iNPCs) from adult human dermal fibroblasts using the non-viral delivery of the pro-neural transcription factors SOX2 and PAX6 [1]. The team then significantly improved this strategy by incorporating DNA-free chemically modified mRNA (cmRNA) technology [2].

Their most recent research applied this approach to the generation of iNPCs from human dermal fibroblasts isolated from patients with adult-onset Huntington's disease; furthermore, they differentiated these iNPCs into a subpopulation of therapeutically relevant DARPP32-expressing striatal GABAergic medium spiny neurons [3]. As described in a recent STEM CELLS article [4], this direct reprogramming platform may represent a new model for investigating neuronal maturation and screening neuronal maturation modifiers for the treatment of Huntington's disease patients.

Monk et al. reported that the neurons differentiated from Huntington's disease-specific iNPCs generated using their laboratory's advanced direct reprogramming strategy possessed a transcriptional profile similar to normal neurons, suggesting that the experimental time course represented by this model system provides an early therapeutic window for investigating disease modifiers before extensive neurodegeneration. Importantly, a subset of Huntington's disease-specific neurons did contain ubiquitinated polyglutamine aggregates, which mark the presence of the mutant Huntington aggregates characteristic of the disease [5].

The Huntington's disease-specific neurons also displayed additional defects, including impaired maturation, altered neurite morphology, and more depolarized resting membrane potentials. Furthermore, in agreement with a previous study [6], the observed reduced levels of brain-derived neurotrophic factor (BDNF) in Huntington's disease-specific neurons, which correlated with increased expanded CAG trinucleotide repeat lengths (another disease characteristic) and earlier symptom onset.

Overall, the authors provide evidence that the striatal GABAergic medium spiny neurons produced by iNPCs directly reprogrammed from fibroblasts isolated from patients with adult-onset Huntington's disease display key pathogenic markers and may represent an exciting alternative to the generation and differentiation of induced pluripotent stem cells (iPSCs) and a means to model pathogenesis and develop novel therapeutic approaches.

For more on the power of direct reprogramming and new Huntington's disease models and associated research, stay tuned to the Stem Cells Portal!


  1. Maucksch C, Firmin E, Butler-Munro C, et al., Non-Viral Generation of Neural Precursor-like Cells from Adult Human Fibroblasts. Journal of Stem Cells and Regenerative Medicine 2012;8:162-170.
  2. Connor B, Firmin E, McCaughey-Chapman A, et al., Conversion of adult human fibroblasts into neural precursor cells using chemically modified mRNA. Heliyon 2018;4:e00918-e00918.
  3. G. Vonsattel JP and DiFiglia M, Huntington Disease. Journal of Neuropathology and Experimental Neurology 1998;57:369-384.
  4. Monk R, Lee K, Jones KS, et al., Directly reprogrammed Huntington's disease neural precursor cells generate striatal neurons exhibiting aggregates and impaired neuronal maturation. STEM CELLS 2021;39:1410-1422.
  5. DiFiglia M, Sapp E, Chase Kathryn O, et al., Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain. Science 1997;277:1990-1993.
  6. Zuccato C and Cattaneo E, Role of brain-derived neurotrophic factor in Huntington's disease. Progress in Neurobiology 2007;81:294-330.