Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1.

Fiammetta Vanoli,Stefania Corti,Paola Rinchetti,Francesca Porro,Valeria Parente

doi:10.1111/jcmm.12606

Abstract

Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans.

Highlights

Clinical presentation– Respiratory distress – Prenatal signs – Neuromuscular features – Central, sensory and autonomic nervous system – Juvenile SMARD1 – IGHMBP2 mutations with a Charcot-Marie-Tooth Disease Type2 (CMT2) phenotypeIGHMBP2 protein Molecular features Animal models Pathogenesis SMARD1 therapy: state of the art and future perspectives– Pharmacological treatment – Gene therapy – Stem cell therapy Conclusions AbstractSpinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin l-binding protein 2, leading to motor neuron degeneration
It has been described the existence in the murine mammalian genome of a major wild-type modifier locus on chromosome 13 (Mnm), that halted motor neuron degeneration and rescued the nmd phenotype [27]. The rescue of their phenotype, given by the introduction in transgenic mice of genes and t-RNAs encoded by this region, suggested the existence of genetic modifiers of SMARD1 phenotype that were independent from the rescue of Ighmbp2 level [25]. Another important aspect to consider is the relationship between the time course of the motor neuron degeneration and the onset of clinical symptoms [19]
We demonstrated the potential therapeutical effect that Neural stem cells (NSCs) obtained from human-induced pluripotent stem cell (iPSC) could have in SMARD1

Summary

Introduction

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a form of SMA with respiratory distress because of diaphragma-. The rescue of their phenotype, given by the introduction in transgenic mice of genes and t-RNAs encoded by this region, suggested the existence of genetic modifiers of SMARD1 phenotype that were independent from the rescue of Ighmbp level [25] Another important aspect to consider is the relationship between the time course of the motor neuron degeneration and the onset of clinical symptoms [19]. In the pathogenesis of nmd mice is the motor neuron loss involved and a progressive cardiomyopathy, caused by the death of the cardiomyocytes and by a functional and morphological alteration of the myocardium [31] To investigate these aspects, Maddatu’s group created a transgenic mouse, which expressed full length Ighmbp c-DNA only in the central nervous system (CNS), including forebrain, cerebellum and spinal cord. We believe that what would allow to reach a clinically significant level in SMARD1 (and other motor neuron diseases as well) in terms of therapeutic efficacy would be the combining of cell, drug and gene therapy [58]

Findings

Conclusions