The overarching objective of this project is to investigate the cellular and molecular mechanisms underlying the disruption in brain development in SMA using patient iPSC-derived neuronal models.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease due to the lack of SMN protein which leads to progressive degeneration of motor neurons in the spinal cord. The majority of SMA 1 children, the more severe end of the spectrum, may exhibit neurodevelopmental comorbidities1. Elevated SMN levels are required during foetal and early postnatal brain development2. Animal studies have shown that growth, development and function of specific brain regions are disrupted when SMN levels are reduced, in particular hippocampus and cerebellum3. Although novel treatments are becoming increasingly available to patients, it is still unclear whether the observed brain-related comorbidities may be equally targeted.
Recent advances in induced pluripotent stem cells (iPSCs) and 3D culture systems have led to the generation of “brain” organoids that resemble several areas of the human brain. Organoids can recapitulate aspects of in vivo brain architecture and physiology and therefore offer new possibilities for modelling neurological disorders and for the development of new therapeutic approaches.