Sviluppo di un approccio con cellule staminali per la terapia delle malattie del motoneurone

Motor neuron diseases (MNDs), such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA), are devastating neurodegenerative disorders in which motor neuron loss results in paralysis and death. Amyotrophic lateral sclerosis (ALS) is the most frequent MNDs that starts in adult life. The ensuing progressive paralysis is typically fatal within a few years, usually owing to failure of the respiratory system. Spinal muscular atrophy (SMA) is among the most common inherited neurological disorders that can cause death in childhood. Currently, there are no effective therapies available for these diseases and they have major impacts on the personal and socio-economic lives of thousands of patients and their caregivers.



Stem cell transplantation offers a potential therapeutic strategy for these diseases through multiple mechanisms, such as 1) replacing lost motor neurons; 2) complementing neuronal replacement with the delivery of neuroprotective factors produced by stem cells; 3) reducing toxic substances in the microenvironment; and 4) replacing other non-neuronal cells.

Recently, we contributed to the development of a cell-mediated approach for treating motor neuron diseases by evaluating neural stem cell (NSC) transplantation in ALS and, for the first time, Spinal Muscular Atrophy models (Corti et al., 2006, 2007 and 2008). These investigations addressed the concept of cell therapy in MNDs rodents and evaluated the biological properties of selected NSC populations.

New technologies in stem cell biology offer alternative cell sources through the reprogramming of adult somatic cells into pluripotent stem cells that can subsequently differentiate into patient-specific neural cells (neurons, motor neurons, and astroglial cells). It was recently reported that the ectopic expression of four transcription factors (Oct4, Sox2, Kfl4, and Myc) in mouse and human somatic cells, such as skin fibroblasts, reprogrammed these cells into a pluripotent state similar to that of embryionic stem cells. These cells were designated induced pluripotent stem cells (iPSCs. Furthermore, the generation of iPSCs from a subject diagnosed with a familial form of ALS and SMA was recently reported.



The project described in this proposal will explore how NSCs derived from iPSCs can be used as in vitro models of ALS and SMA and how they can be used to develop therapeutic approaches for these diseases. Our aim is to create a new platform for studying the biology of normal and diseased human neural cells that will enhance our understanding of the pathogenesis of MNDs and accelerate the development of therapies for motor neuron and other neurological diseases.