Reprogramming of iPSCs has given rise to the emergence of reprogramming approaches that target other types of cells including those of meso-, endo- and ectodermal origin — for example, the generation of functional neurons from fibroblasts which has been reported in a number of recent studies. These are, potentially, therapeutically powerful strategies to target severe and elusive diseases.
One such disease is Parkinson’s, a disorder of the nervous system affected by the death of neurons and impaired dopamine signaling. Work from the Karolinska Institutet with collaborators at Stanford University, the University of Vienna and Malaga University described, for the first time, a new approach to treating Parkinson’s which merges cell therapy alongside genetic reprogramming of cells for enhanced therapeutic targeting. The work was published in Nature Biotechnology this week.
In the study, the authors demonstrated that human astroglia can be reprogrammed into induced neurons capable of expressing midbrain–specific transcription factors as well as typical dopaminergic markers, resulting in mature neuronal morphology and functionality.
To reprogram the cells, the authors used a mixture of transcription factors – NEUROD1, ASCL1 and LMX1A – and the microRNA miR218, which were lentivirally transfected into target cells. By treating the reprogrammed cells with growth factors (TGFβ1) and small molecules (VPA, Dec, SB, LDN, AA, CT and purmorphamine), the cells were shown to resond to cues indicating chromatin remodeling and midbrain development, hallmarks of mature neurons.
That the reprogramming could be achieved in vivo in an animal model of Parkinson’s was a remarkably positive step toward future potential clinical therapies for Parkinson’s disease.