Promising Outcomes of Original Grant:
We have established a new procedure to directly convert skin fibroblasts (a type of cell) from pre-clinical models into induced dopaminergic (iDA) neurons. We have provided results showing that iDA neurons are functional and competent to produce and release dopamine and to establish synapses. Moreover, after transplantation in a model of Parkinson’s disease, iDA neurons survive and integrate in the host tissue and support a significant behavioral rescue of the motor symptoms.
Objectives for Supplemental Investigation:
To date, adult human fibroblasts have been difficult to convert into iDA neurons. We plan to establish a superior protocol of genetic reprogramming suitable for converting human adult fibroblasts into functional iDA neurons with high efficiency. Human adult fibroblast-derived DA neurons will be tested for their ability to have an excitable membrane, establish synapses and produce and release dopamine. In addition, human iDA neurons will be transplanted in a model of Parkinson’s disease to test their capability of reversing the diseased state and re-establishing a functional dopaminergic system. Finally, some critical aspects of these neurons will be studied in order to ensure their complete safety profile in the prospective of any possible therapeutic application.
Importance of This Research for the Development of a New PD Therapy:
This study will establish efficient protocols for generating iDA neurons through direct conversion of adult fibroblasts from healthy donors as well as people with idiopathic or genetic forms of Parkinson’s disease. Through this procedure, it will be, then, possible to facilitate and accelerate the production of disease-affected iDA neurons for studying in the dish multiple pathogenetic mechanisms of PD with relevant patient’s cells. In addition, iDA neurons will be explored as a superior source for cell replacement therapeutic approaches in PD in order to restore a dopaminergic neuronal network competent to re-establish dopamine function when necessary.