Hip displacement management in spinal muscular atrophy in the era of disease modifying therapies: a Delphi consensus study in the UK.

Spinal Muscular Atrophy: A Deficiency in a Ubiquitous Protein; a Motor Neuron-Specific Disease

Buying time for infants with spinal muscular atrophy

AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice

Bifunctional RNAs Targeting the Intronic Splicing Silencer N1 Increase SMN Levels and Reduce Disease Severity in an Animal Model of Spinal Muscular Atrophy

SMA is a motor neuron disease characterised by generalised muscle atrophy and weakness. It is caused by the dysfunction and eventual death of motor neurons, due to deletions of SMN1...

Dual Masking of Specific Negative Splicing Regulatory Elements Resulted in Maximal Exon 7 Inclusion of SMN2 Gene

SMA THERAPIES II AND BIOMARKERS: P.259SMN protein levels before and after treatment with RG7916 in type 1, 2 and 3 SMA patients compared to healthy subjects

To conduct a systematic review and evaluate the quality of evidence for interventions to prevent hip displacement in children with cerebral palsy (CP). A systematic review was performed using American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were completed in seven electronic databases. Studies were included if participants had CP and the effectiveness of the intervention was reported using a radiological measure. Results of orthopaedic surgical interventions were excluded. Twenty-four studies fulfilled the inclusion criteria (4 botulinum neurotoxin A; 2 botulinum neurotoxin A and bracing; 1 complementary and alternative medicine; 1 intrathecal baclofen; 1 obturator nerve block; 8 positioning; 7 selective dorsal rhizotomy). There was significant variability in treatment dosages, participant characteristics, and duration of follow-up among the studies. Overall, the level of evidence was low. No intervention in this review demonstrated a large treatment effect on hip displacement. The level and quality of evidence for all interventions aimed at slowing or preventing hip displacement is low. There is currently insufficient evidence to support or refute the use of the identified interventions to prevent hip displacement or dislocation in children and young people with CP. High-quality evidence on prevention of hip displacement is lacking. No recommendations can be made for preventing hip displacement in children with cerebral palsy because of poor-quality evidence. High-quality, prospective, longitudinal studies investigating the impact of interventions on hip displacement are required.

93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) – clinical picture (6–8 April 2001, Naarden, The Netherlands)

The survival of motor neuron (SMN) protein, responsible for the neurodegenerative disease spinal muscular atrophy (SMA), oligomerizes and forms a stable complex with seven other major components, the Gemin proteins. Besides the SMN protein, Gemin2 is a core protein that is essential for the formation of the SMN complex, although the mechanism by which it drives formation is unclear. We have found a novel interaction, a Gemin2 self-association, using the mammalian two-hybrid system and the in vitro pull-down assays. Using in vitro dissociation assays, we also found that the self-interaction of the amino-terminal SMN protein, which was confirmed in this study, became stable in the presence of Gemin2. In addition, Gemin2 knockdown using small interference RNA treatment revealed a drastic decrease in SMN oligomer formation and in the assembly activity of spliceosomal small nuclear ribonucleoprotein (snRNP). Taken together, these results indicate that Gemin2 plays an important role in snRNP assembly through the stabilization of the SMN oligomer/complex via novel self-interaction. Applying the results/techniques to amino-terminal SMN missense mutants that were recently identified from SMA patients, we successfully showed that amino-terminal self-association, Gemin2 binding, the stabilization effect of Gemin2, and snRNP assembly activity were all lowered in the mutant SMN(D44V), suggesting that instability of the amino-terminal SMN self-association may cause SMA in patients carrying this allele.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.

Background Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009. Objectives To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.ClinicalTrials.gov) (8 March 2011) to identify additional trials that had not yet been published. Selection criteria We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis.The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. Data collection and analysis Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. Main results One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in 2011. Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. Authors' conclusions No drug treatment for SMA type I has been proven to have significant efficacy.

Spinal muscular atrophy (SMA) is a rare genetic disease resulting in loss of motor function and, in severe cases (e.g., SMA type 1), infantile death. While treatments like nusinersen and onasemnogene abeparvovec improve prognosis for patients with SMA, costs for these medications can contribute to economic burden. Direct costs were compared for onasemnogene abeparvovec, a one-time gene replacement therapy, versus nusinersen, a lifelong therapy, for patients with SMA type 1 and/or three or more survival motor neuron 2 (SMN2) gene copies in the Netherlands. A cost comparison analysis model of 1-year incident patient population from the Netherlands was used to compare costs of onasemnogene abeparvovec versus nusinersen for patients eligible for onasemnogene abeparvovec immediately after diagnosis. Multiple analyses were conducted for economic outcomes (e.g., base-case, break-even, deterministic sensitivity, probabilistic sensitivity, scenario analyses). Cost differences of -€2.9million (undiscounted) and -€1.5million (discounted) per patient with SMA type 1 treated with onasemnogene abeparvovec versus nusinersen over a 20-year time horizon were identified (base-case). Reduced costs with onasemnogene abeparvovec versus nusinersen were evident after 8.25 years. Onasemnogene abeparvovec was less costly than nusinersen after 8.25 years of treatment of patients with SMA type 1 in the Netherlands.

Targeting splicing in spinal muscular atrophy

Investigating neurodegenerative diseases with small molecule modulators Reka Rebecca Letso Elucidation of the mechanisms underlying cell death in neurodegenerative diseases has proven difficult, due to the complex and interconnected architecture of the nervous system as well as the often pleiotropic nature of these diseases. Cell culture models of neurodegenerative diseases, although seldom recapitulating all aspects of the disease phenotype, enable investigation of specific aspects of these disease states. Small molecule screening in these cell culture models is a powerful method for identifying novel small molecule modulators of these disease phenotypes. Mechanistic studies of these modulators can reveal vital insights into the cellular pathways altered in these disease states, identifying new mechanisms leading to cellular dysfunction, as well as novel therapeutic targets to combat these destructive diseases. Small molecule modulators of protein activity have proven invaluable in the study of protein function and regulation. While inhibitors of protein activity are relatively common, small molecules that can increase protein abundance are quite rare. Small molecule protein upregulators with targeted activities would be of great value in the study of the mechanisms underlying many loss of function diseases. We developed a highthroughput screening approach to identify small molecule upregulators of the Survival of Motor Neuron protein (SMN), whose decreased levels cause the neurodegenerative disease Spinal Muscular Atrophy (SMA). We screened 69,189 compounds for SMN upregulators and performed mechanistic studies on the most active compound, a bromobenzophenone analog designated cuspin-1. Mechanistic studies of cuspin-1 revealed that increasing Ras signaling upregulates SMN protein abundance via translation, an effect which may be associated with the translational regulator mammalian target of rapamycin (mTOR). These findings suggest that controlled modulation of the Ras signaling pathway may benefit patients with SMA. Small molecule modulators of a disease phenotype, such as cell death, have the potential to reveal novel mechanisms regulating disease processes. This was exemplified by a screen for small molecule inhibitors of cell death caused by a pathogenic, misofolded mutant huntingtin protein in a cell culture model of Huntington’s Disease (HD). These cell death inhibitors were found to target protein disulfide isomerase (PDI), an oxidoreductase known to be important in endoplasmic reticulum quality control of protein folding. However, our studies utilizing the small molecule PDI inhibitors determined that the cell death observed in this system was due to a pro-apoptotic function of PDI involving proteins of the mitochondrial outer membrane. We have begun studies aimed at identifying the binding mode of these novel small molecule inhibitors of PDI, in efforts to develop more potent and efficacious analogs for testing in animal models of HD. These studies have helped defined a novel mechanism linking protein misfolding to cell death, and may prove to be relevant to a broader range of protein misfolding diseases. Table of contents List of Figures and Tables v Acknowledgements vii Chapter 1: Spinal Muscular Atrophy 1 I. Treating inherited neurodegenerative diseases 1 a. Gain of function neurodegenerative diseases 2 b. Loss of function neurodegenerative diseases 5 II. Spinal Muscular Atrophy Disease 7 a. SMA disease pathogenesis 8 b. SMA disease phenotypes 9 c. Genetics of SMA 10 d. Animal models of SMA 15 III. Survival of Motor Neuron protein: Structure and Function 23 a. SMN expression and localization 23 b. SMN domain structure and functions 25 c. SMN interacting partners 28 i. The SMN Complex 29 ii. SMN interacts with hnRNP Q/R and β-actin mRNA 30 iii. SMN and profilin 32 iv. The possible role of actin dynamics in Spinal Muscular Atrophy 33 d. Neuronal function(s) of SMN 34 IV. Current state of small molecule therapeutics for SMA 46