Lymphoid Organ Architecture and Hematopoiesis Disruption in Spinal Muscular Atrophy: Therapeutic Rescue by SMN Restoration

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of the SMN1 gene, reduced levels of SMN protein, and motor neuron degeneration. However, increasing evidence shows that SMA is a multisystemic disease with immune system involvement. We investigated how SMN deficiency affects lymphoid organ development and function using a severe SMA mouse model (SMNΔ7) and postmortem human fetal and postnatal tissues lacking SMN1 and carrying one or two SMN2 copies, consistent with type 0–I SMA. Histology, immunostaining, and flow cytometry were used to examine tissue architecture and immune cell composition. SMNΔ7 mice displayed thymus, spleen, and bone marrow abnormalities, including mislocalization of T- and B-cells and expansion of resident macrophages. Bone marrow analysis revealed impaired B-cell development, suggesting intrinsic hematopoietic defects rather than apoptosis. Early treatment with a nusinersen-like antisense oligonucleotide, administered intracerebroventricularly or subcutaneously, restored SMN2 splicing, improved survival, motor function, and prevented lymphoid pathology. Human SMA samples exhibited similar, though milder, splenic alterations compared to SMNΔ7 mice, while thymic organization remained largely preserved. These findings demonstrate that SMN deficiency disrupts lymphoid organ development through defective bone marrow output and impaired immune cell maturation. Early SMN restoration prevents these abnormalities, highlighting immune dysfunction as a key component of SMA pathology.

This work was supported by grants from the Ministerio de Ciencia e Innovación (MCIN)/FEDER (grant number: PID2021-122785OBI00 to JC and OT, and PID2021-126820OB-I00 to Olga Tapia), and Fundació La Marató de 3Cat (grant number 202005-30) to JC. PG is an FPI fellow from the MCIN (PRE2022-102424). GL was supported by the European Union’s Horizon 2020 research and innovation program under the María Sklodowska-Curie grant (H2020Marie Sklodowska-Curie actions) agreement nº 9561859 (SMABEYOND ITN to EFT). LM-E holds a predoctoral FI-SDUR-2023 fellowship (00036).