Open‐labelled study to monitor the effect of an amino acid formula on symptom management in children with spinal muscular atrophy type I: The SMAAF pilot study

Background: An increasing number of families of spinal muscular atrophy (SMA) children are incorporating an amino acid-based enteral formula into their child’s feeding regimens. Other components of the amino acidbased formula include added carbohydrates, electrolytes, and probiotics. Due to insufficient evidenced based research regarding the efficacy of the formula clinicians are unable to prescribe or endorse. The aim was to assess the tolerability and safety of an adapted version of the traditional SMA amino acid formula (SMAAF) in children with SMA Type I.Methods: Children with SMA Type I were recruited if exclusively enterally fed and experiencing at least one gastrointestinal symptom (reflux, vomiting, constipation and/ or diarrhoea). Children were transferred on to an amino acid formula (Neocate® Syneo™- Nutricia) for eight weeks. Primary outcome was feed tolerance, measured weekly by telephone consultation to monitor gastrointestinal tolerance.Results: Fourteen children were recruited, mean age 4.1 years (1.2SD). The mean resting energy expenditure measured by indirect calorimetry was 51kcal/ kg (7SD). The most common gastrointestinal complaint prior to switching to SMAAF was constipation (n=12). Ten of the 12 children who reported constipation symptoms were prescribed stool softeners/laxatives daily and after 8 weeks on SMAAF, 8 of these 10 (80%) children reduced or discontinue stool softener/ laxatives. Parents reported an improvement with reflux symptoms in 4 out of 5 children whilst on SMAAF.Conclusion: Our pilot study suggests that children with SMA Type I who are displaying gastrointestinal symptoms, such as constipation and reflux may benefit from an amino acid formula

Argument Structure and Learnability: Is a Solution in Sight?

Proceedings of the Twenty-Second Annual Meeting of the Berkeley Linguistics Society: General Session and Parasession on The Role of Learnability in Grammatical Theory (1996

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<p>In her Beijing lectures, Melissa Bowerman presents a lucid introduction and account of her research on a range of topics: how children acquire the semantics of spatial terms, how they construct categories and acquire the semantics of nouns, and how they master the semantics of verbs in early language acquisition. Bowerman also covers the learning of argument structure and expressions of end-state, with special attention to the adult speech that guides children, and hence also the role of typology in acquisition; how cross-linguistic variation affects, for example, how speakers represent ‘cutting’ and ‘breaking’ in different languages, and the relation of the Whorfian Hypothesis to cross-linguistic variations in the semantics of languages. Bowerman’s over-riding concern throughout is with how children come to master the first language being spoken to them by their parents and caregivers.</p

The Relationship between Body Composition, Fatty Acid Metabolism and Diet in Spinal Muscular Atrophy

Acknowledgments: I.B. received a studentship from SMA Angels Charity. M.B.’s SMA research isfunded by SMA Angels Charity, Muscular Dystrophy UK, Action Medical Research and SMA UK. S.H.P.’s SMA research is funded by SMA Europe and Anatomical Society.Peer reviewedPublisher PD

Enhanced expression of the human Survival motor neuron 1 gene from a codon-optimised cDNA transgene in vitro and in vivo

Spinal muscular atrophy (SMA) is a neuromuscular disease particularly characterised by degeneration of ventral motor neurons. Survival motor neuron (SMN) 1 gene mutations cause SMA, and gene addition strategies to replace the faulty SMN1 copy are a therapeutic option. We have developed a novel, codon-optimised hSMN1 transgene and produced integration-proficient and integration-deficient lentiviral vectors with cytomegalovirus (CMV), human synapsin (hSYN) or human phosphoglycerate kinase (hPGK) promoters to determine the optimal expression cassette configuration. Integrating, CMV-driven and codon-optimised hSMN1 lentiviral vectors resulted in the highest production of functional SMN protein in vitro. Integration-deficient lentiviral vectors also led to significant expression of the optimised transgene and are expected to be safer than integrating vectors. Lentiviral delivery in culture led to activation of the DNA damage response, in particular elevating levels of phosphorylated ataxia telangiectasia mutated (pATM) and ?H2AX, but the optimised hSMN1 transgene showed some protective effects. Neonatal delivery of adeno-associated viral vector (AAV9) vector encoding the optimised transgene to the Smn2B/- mouse model of SMA resulted in a significant increase of SMN protein levels in liver and spinal cord. This work shows the potential of a novel codon-optimised hSMN1 transgene as a therapeutic strategy for SMA

Therapeutic strategies for spinal muscular atrophy: SMN and beyond

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery

Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis:Converging roads to therapeutic development

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72). However, it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadic ALS. Beyond genetic interactions, accumulating evidence further suggests that both diseases share common pathological identities such as intrinsic muscle defects, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuron excitability and selective motoneuron vulnerability. Identifying common molecular effectors that mediate shared pathologies in SMA and ALS would allow for the development of therapeutic strategies and targeted gene therapies that could potentially alleviate symptoms and be equally beneficial in both disorders. In the present review, we will examine our current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases

Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA)

Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritised as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles, and molecular pathways, including metabolism of proteins and vesicle-mediated transport; both of which converge on ER-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases

Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy [preprint]

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies