The role of an altered neuromesodermal specification in the initiation of Spinal Muscular Atrophy

• Applicant: Dr. Natalia Rodriguez-Muela
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Developmental Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560017257

How certain neuronal subpopulations become highly vulnerable upon ubiquitously expressed disease-causing mutations is an unresolved fundamental question in spinal muscular atrophy (SMA), and in the neuroscience scientific community in general, that is halting the discovery of efficacious treatments. Why are motor neurons (MNs) primarily affected, and why do not all MNs degenerate to the same degree? Do some MNs harbor intrinsic marks that make them prone to degenerate? Does a developmental defect trigger the onset of the disease? SMA has been investigated primarily from a post-natal stage, focusing mainly on the pathology of postmitotic MNs or mature muscle cells. However, evidence from SMA mouse models resembling patients affected with SMA type I, recent studies in fetus and our own findings using in vitro human-derived complex 3D models are revealing that degeneration occurs already during early development. In addition, documentation on current therapeutic approaches highlights the importance of treating patients as early as possible. Importantly, although the three approved therapies for SMA have drastically delayed disease progression, there is a high variability in the patient’s response to the treatment, they can cause severe adversary effects and none of them constitutes a definitive cure, particularly in individuals with only 2 SMN2 copies. These data have made us question whether we need to redefine “early” treatment for SMA, and whether there is “something else” contributing to drive the pathology and therefore only restoring SMN functionality in the most severe cases would not be enough. Filling up those gaps will be essential to develop combinatorial therapies to halt the degeneration. This study hypothesizes that early developmental defects precede, and are responsible for, the selective neuromuscular degeneration in SMA, at least in the most severe forms. We will address this hypothesis taking advantage of the first isogenic patient-derived induced pluripotent stem cell model for SMA and a complex spinal cord organoid system -which enables the formation of neural and muscle tissues- that we generated, in combination with the SMNΔ7 mouse model. We will explore a potentially aberrant stem cell lineage fate commitment during the earliest phases of development. In addition, we will interrogate whether alterations in neural and mesodermal specification programs characterize SMA type I and result in faulty MNs and muscle cells, as well as the underlying molecular mechanisms in the attempt to prove causation. Understanding when and in which cell type the disease first manifests remains a challenge that, once overcome, should enable the optimization of therapies and even their tailoring to specific phases or types of the disease. Altogether, the proposed study will lay the foundation for potentially revisiting the fundamental biology behind SMA etiology and treatment.

• DFG Programme: Research Grants