Motoneuron Transplantation Rescues the Phenotype of SMARD1 (Spinal Muscular Atrophy with Respiratory Distress Type 1)

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a fatal form of infantile motoneuron disease. There is currently no effective treatment, although motor neuron replacement is a possible therapeutic strategy. We transplanted purified motor neurons into the spinal cord of nmd mice, an animal model of SMARD1. We also administered pharmacological treatment targeting the induction of axonal growth toward skeletal muscle target. At the end stage of the disease, donor-derived motor neurons were detected in the nmd anterior horns, extended axons into the ventral roots, and formed new neuromuscular junctions. These data correlated with improved neuromuscular function and increased life spans. The neuroprotective effect was associated with a reduction in proinflammatory molecules in treated spinal cords. This is the first report that functional restoration of motor units with transplanted motoneurons is feasible in an animal model of a human motoneuron disease, opening up new possibilities for therapeutic intervention.

Human motor neuron generation from embryonic stem cells and induced pluripotent stem cells

“…This crucial step has been recently demonstrated to be feasible, although is difficult to achieve in vitro [10][11][12]53]. After isolation from tissue culture, motor neurons maintain their polarity and grow processes with the characteristic features of dendrites and axons.…”

“…Stem cell-derived motor neurons show increasing promise as research tools in disease modeling and highthroughput molecular and drug screens [6,7], as well as in devising therapeutic strategies for neurodegenerative disorders, for example as replacements for degenerating cells in the CNS [8][9][10][11][12]. The technical and ethical challenges of obtaining spinal motor neurons from fetal or post-mortem human tissues significantly complicate this area of research [13,14].…”

The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: A systematic review

“…On the other hand, stem cell-mediated therapeutic strategies, such as the ones based on the use of induced pluripotent stem cells (iPSCs), exploit the generation and the transplantation of the specific cell type that is impaired in the disease, therefore providing healthy motor neurons which are degenerating in SMARD1. In our experience, gene therapy is more efficient when administered at pre-symptomatic stages [39,40] while stem cell transplantation can exert positive effects in symptomatic patients through multiple mechanisms, including neuroprotection and cell replacement. Our research group has recently reported that cell transplantation can ameliorate the disease phenotype in nmd mice, a SMARD1 model [39,40].…”

“…In our experience, gene therapy is more efficient when administered at pre-symptomatic stages [39,40] while stem cell transplantation can exert positive effects in symptomatic patients through multiple mechanisms, including neuroprotection and cell replacement. Our research group has recently reported that cell transplantation can ameliorate the disease phenotype in nmd mice, a SMARD1 model [39,40]. Reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs) provides unprecedented access to stem cells for therapeutic approaches.…”

Motor Neuron Disease and Stem Cell Approach for Its Remediation

“…Intrathecal administration of NSCs in mice model of SMA induces the growth factors including GDNF, BDNF and neurotrophin. Engrafted animal showed 39% increase in lifespan and 8% of total transplanted cells express choline acetyl transferase [35]. Human NSCs are also used for ex-vivo delivery of protease gene for the treatment of Alzheimer's disease (AD) because it is caused by the increase levels of both soluble and insoluble Aβ peptides.…”