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Direct reprogramming for HD Disease Modelling

Periodic Reporting for period 1 - DISMOD-HD (Direct reprogramming for HD Disease Modelling)

Reporting period: 2017-05-15 to 2019-05-14

The objective of this project was to generate a new system to model Huntington’s Disease in human neurons, in vitro. To do so we have planned to use human primary fibroblasts donated by healthy donors or Huntington’s Disease (HD) patients and reprogram them into medium spiny neurons (MSNs), which are the neuronal population most affected by Huntington’s Disease.
The aim of the generation of this new model system is to allow us to study the characteristics of human neurons, both healthy and with HD, and thus to find and understand new pathological mechanisms that are leading to neuronal death in patients.
During this project we have achieved the generation of MSNs in vitro, via direct reprogramming of human primary fibroblasts. However, we reached the end of the grant period before we could generate MSNs from fibroblasts of HD patients. This delay in the achievement of the proposed goals was due to unforeseen technical difficulties in the protocol for efficient reprogramming of human fibroblasts into MSNs.
In conclusion, it was possible to reach the one of the proposed milestones, which saw the definition of a reprogramming cocktail for the direct conversion of human primary fibroblasts into MSNs in vitro, in the absence of antibiotic selection or pro-survival factors. This work constitutes an important stepping stone for further optimisation of highly efficient reprogramming strategies, aimed at studying human neurodegenerative disorders in vitro.