Spinal muscular atrophy with respiratory distress type I (SMARD1) is an infantile autosomal recessive genetic disease, caused by mutations in the IGHMBP2 gene which cause the reduction of the ubiquitous protein IGHMBP2. SMARD1 is characterized by a progressive loss of motor neurons (MNs), leading to a muscular weakness and atrophy, and by a severe respiratory distress caused by diaphragm palsy. Currently, there are no effective therapies for this disease.

Evaluate the therapeutic effect of iPSC-derived neural stem cells on the neuropathological hallmarks of SMARD1 disease.

We generated NSCs from pluripotent stem cells (iPSCs) of healthy controls then selected for the expression of the specific molecules LewisX, CXCR4 and β1-integrin. We administered intrathecally the NSCs selected into SMARD1 mice (nmd) at postnatal day 1 after a previous evaluation in NOD-SCID mice. We verified the properly migration of LeX+CXCR4+β1+ NSCs from the central nervous system and the engraftment in the spinal cord parenchyma.

To evaluate the beneficial role of the treatment we studied the overall appearance of nmd mice and the effect on muscles, neuromuscular junctions (NMJ) and MNs.

The transplanted LeX+CXCR4+β1 NSCs engrafted in the spinal cord of nmd mice with a significant improvement in the phenotypic hallmarks of the disease.

Treated nmd mice showed ameliorate overall appearance, recovery of neuromuscular functions and increase in lifespan. The NSC subpopulation protected endogenous MNs from degeneration and it also had a beneficial effect at the periphery, promoting NMJ maintenance. Moreover, the specific treatment positively affected muscular tissues, that presented an ameliorated muscle fiber morphology and organization and less fatty infiltration.

Overall, we demonstrated that transplantation of a specific human iPSC-derived NSC subpopulation, selected to enhance migration, survival and engraftment, has a beneficial role in modifying the course of SMARD1 pathology supporting NSC-mediated therapy.