New targets for combinatorial therapy in Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a severe neuromuscular pathology caused by mutations or deletions in the SMN1 gene, leading to progressive degeneration of motor neurons (MNs) and muscle atrophy. Even if the available SMN-targeted therapies have significantly ameliorated patient outcomes, their efficacy remains limited, particularly in advanced stages or when treatment is delayed. Therefore, complementary therapeutic approaches are needed to further improve disease management. In this study, we explored two potential therapeutic avenues: an SMN-independent strategy targeting in particular muscular district, and an SMN-dependent approach addressing pathways related to mitochondrial dysfunction. First, we investigated the efficacy of the growth hormone-releasing hormone (GHRH) agonist MR- 409 in SMNΔ7 mice, a severe SMA model. Daily administration from postnatal day 2 (P2) to P12 determined significant improvements in body weight and motor performance, along with enhanced muscle fiber size and neuromuscular junction maturation. Molecular and histological analyses further revealed increased levels of myogenic markers, decreased atrophy-related proteins, delayed MN loss, and reduced spinal cord inflammation, suggesting a protective role of MR-409 in SMA. In the second part of the study, we examined mitochondrial dysfunction as a potential therapeutic target by identifying SMN1-anticorrelated mitochondrial genes. Among these, Gcsh, encoding a key component of the glycine cleavage system (GCS), resulted significantly upregulated in SMNΔ7 mouse spinal MNs at early disease stages. Immunohistochemical analysis confirmed increased GCSH protein expression in MNs and astrocytes, accompanied by alterations in glycinergic system components and progressive morphological changes in Renshaw Cells, interneurons involved in MN recurrent inhibition. These findings suggest that dysregulation of glycinergic signaling could contribute to SMA pathophysiology. Overall, these insights provide a basis for novel potential combinatorial approaches to complement existing treatments, ultimately aiming to ameliorate patient outcomes.