Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

Abstract

Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

Emerging therapies and challenges in spinal muscular atrophy

“…These include functional and structural cardiac defects,66 abnormal development of the gastrointestinal tract, liver, and spleen,64, 67, 68 and irregular bone remodeling and skeletal pathology 69. These findings suggest that successful treatment of SMA may require systemic targeting of a range of affected tissues.…”

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

“…Subsequent years also witnessed a series of in vivo studies employing phosphorodiamidate morpholino oligonucleotides (PMOs) targeting ISS-N1. 13,15,51–54 These studies provided additional independent validations of the efficacy of ISS-N1-targeting ASOs.…”

“…13,15,48–54,61–72 Initially, the 2′OMe ISS-N1-targeting ASO 43 increased SMN protein in the central nervous system (CNS) and improved motor function in the Δ7 mouse. 61 This finding led to studies from Krainer and colleagues, and independently from the Burghes (The University of Ohio School of Medicine, Columbus, OH, USA) and Muntoni groups (University College London, London, UK), to further explore the efficacy of the ISS-N1 inhibitor, albeit they used contrasting delivery strategies and ASOs of different lengths and chemistries.…”

Diverse role of survival motor neuron protein

“…SMN reduction affects the development and function of the cardiovascular system [276–278], lungs [278,279], bone [280], intestine [278,281,282], liver [283,284], pancreas [285], spleen [286] and testis [57]. Although the exact mechanism by which SMN influences the development and function of these organs is a matter of future investigation, it is clear that in addition to the nervous system the effective treatments for SMA will need to address peripheral organ defects as well.…”