The role of vascular pathology in SMA: implications for pathogenesis and treatment

Spinal muscular atrophy (SMA) has become a paradigm for precision medicine following the development of transformative therapies targeting the disease-causing deficiency of survival motor neuron (SMN) protein. As more than 98% of SMA cases arise from mutations in the SMN1 gene, restoration of SMN expression through nusinersen (Spinraza; Biogen, Cambridge, MA), risdiplam (Evrysdi; Roche, Basel, Switzerland) and onasemnogene abeparvovec (Zolgensma and Itvisma; AveXis, Novartis, Chicago, IL) has produced unprecedented clinical benefits and established SMA as the first treatable motor neuron disease. To date, therapeutic success has focused on rescuing motor neurons, the principal site of clinical pathology. However, growing evidence indicates that SMA is a multisystem disorder in which pathological changes extend beyond the motor unit. In particular, vascular pathology has emerged as a recurring feature across numerous affected tissues. Vascular abnormalities have been identified throughout the neuromuscular system, including the spinal cord and skeletal muscle, as well as in systemic organs such as the heart, kidney, gastrointestinal tract and spleen. Experimental studies suggest that endothelial dysfunction is a direct consequence of SMN deficiency, impairing angiogenesis, vascular maturation and vessel stability, while patient-derived biomarkers, including retinal vascular imaging and elevated circulating endothelial cells (CEC), provide evidence of ongoing endothelial dysfunction in patients. These vascular abnormalities have the potential to compromise tissue perfusion, promote local hypoxia, disrupt barrier integrity and enhance inflammatory signaling, thereby exacerbating disease progression. Collectively, the evidence suggests that SMN-dependent vascular pathology may represent an under-recognized feature of SMA pathogenesis and a potential therapeutic target. Here, we review the current evidence for vascular pathology in SMA, discuss its implications for disease progression, long-term patient outcomes and therapeutic response, and consider whether vascular abnormalities are adequately addressed by existing SMN-restorative therapies.