Assessing the Therapeutic Potential of iDA Neuronal Cells in Autologous Strategy
Rapid Response Innovation Awards, 2011
The research from this grant has continued with the supplementary grant:
We have shown recently that three transcription factors can promote the conversion of skin fibroblasts into induced dopaminergic neuronal (iDAN) cells with remarkable functional activities. Herein, we plan to test the therapeutic potential of iDAN cells in treating a pre-clinical model of PD. iDAN cells will be generated from the same diseased pre-clinical models and then transplanted in the brain in order to replace those neurons lost in the disease. We will evaluate whether iDAN cells will integrate in the host brains and promote the rescue of the motor deficits.
Skin fibroblasts will be biopsied from pre-clinical models treated unilaterally with 6-OHDA to trigger dopaminergic cell los and PD motor symptoms. Fibroblasts will be infected with a cocktail of lentiviruses expressing the three reprogramming genes Mash1, Nurr1 and Lmx1a and converted into iDAN cells. Reprogrammed neurons will be collected and transplanted back to the pre-clinical models both in an autologous or heterologous setting. This strategy will allow us to examine the impact of autologous transplantation in symptoms recovery avoiding the need of a severe immunosuppressive treatment. Grafted pre-clinical models will be tested for the rescue of locomotor deficits. Then, pre-clinical models will be analyzed for survival, integration and maturation of the grafted iDAN cells. iDAN cell activity will be also measured by electrophysiological recordings on brain slices together with quantification of dopamine release.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
Cell-based therapies for treating PD have a strong rational and were shown already to be beneficial for the patients. However, an ideal source of renewable neurons for this application is still lacking. Herein, we aim to test reprogrammed neurons as an improved source of functional DA neurons for cell therapy. Indeed, they have innovative properties as the possibility to be individual-specific and their lack of tumorigenic potential. Thus, these cells might offer a new therapeutic option which potential we will test in this project.
iDAN cells will be transplanted in a pre-clinical model of PD in both autologous or heterologous settings. Thus, we will learn whether these neurons will integrate and promote therapeutic benefits in these pre-clinical models. Furthermore, we will appreciate the advantages of using autologous cells which do not required the use of a strong and prolonged immunosuppression treatment. Finally, iDAN cell functional properties will be investigated measuring electric activity and dopamine release directly in the host tissue.
Head of Research Unit at San Raffaele Scientific Institute
Location: Milan, Italy