Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy.
Ontology highlight
ABSTRACT:
SUBMITTER: Meijboom KE
PROVIDER: S-EPMC8410072 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-05-14 | GSE150563 | GEO
Project description:We used an in-depth and parallel approach combining proteomics, transcriptomics and the drug pertubational dataset Connectivity Map (CMap) to identify differentially expressed (DE) transcripts and proteins in skeletal muscle of the severe Taiwanese Smn-/-;SMN2 SMA mice that could potentially be restored by known and available pharmacological compounds. This strategy uncovered several potential therapeutic candidates, including harmine, which was further evaluated in cell and animal models, showing an ability to restore molecular networks and improve several disease phenotypes, including SMN expression and lifespan.
2020-05-14 | GSE150510 | GEO
Project description:In neurodegenerative disorders, effective treatments are urgently needed, along with methods to determine whether treatment worked. In this review, we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is caused by loss of the survival motor neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving toward clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression.
| S-EPMC3876415 | biostudies-literature
Project description:The motor neuron disease spinal muscular atrophy (SMA) is caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1). Alone, such mutations are embryonically lethal, but SMA patients retain a paralog gene, SMN2, that undergoes alternative pre-mRNA splicing, producing low levels of SMN protein. By mechanisms that are not well understood, reduced expression of the ubiquitously expressed SMN protein causes an early-onset motor neuron disease that often results in infantile or childhood mortality. Recently, striking clinical improvements have resulted from two novel treatment strategies to increase SMN protein by (a) modulating the splicing of existing SMN2 pre-mRNAs using antisense oligonucleotides, and (b) transducing motor neurons with self-complementary adeno-associated virus 9 (scAAV9) expressing exogenous SMN1 cDNA. We review the recently published clinical trial results and discuss the differing administration, tissue targeting, and potential toxicities of these two therapies. We also focus on the challenges that remain, emphasizing the many clinical and biologic questions that remain open. Answers to these questions will enable further optimization of these remarkable SMA treatments as well as provide insights that may well be useful in application of these therapeutic platforms to other diseases.
| S-EPMC6063504 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies.
| S-EPMC7408870 | biostudies-literature
Project description:The survival motor neuron 1 (SMN1) gene is the causative gene for the spinal muscular atrophy (SMA) disease, the first genetic cause of infant mortality. It affects primarily motor neurons which are the targets of the approved genetic therapies aimed to compensate for the loss of SMN1. However, the limitations of these therapies are now evident since they are not cures, and alternative strategies need to be investigated. Because of the ubiquitous and multifunctional roles of SMN1 in the cell, deeper understanding of the molecular mechanisms underlying intrinsic abnormalities of the different tissues affected by SMA is crucial for the development of new therapeutic approaches. Here we used a muscle specific genetic mouse model for the identification of key cellular processes associated to SMN1 loss, at single myofiber level. We found that mitochondrial dysfunction is a key pathogenetic event in SMA: mitochondria are abnormal with internal degenerated cristae. The ultrastructural changes are coincident with alterations in ROS levels by monoamine oxidase A and Ca2+ homeostasis. Interestingly, the improvements of the myopathic phenotype of the muscle-specific SMA model mice by transplantation of amniotic fluid stem (AFS) cells led to restore mitochondrial function. Our data suggest that a mitochondria-targeting therapy may represent a complementary and broad treatment strategy to further optimize the current treatment.
2023-03-08 | GSE207890 | GEO
Project description:Spinal muscular atrophy (SMA) is a potentially devastating and lethal neuromuscular disease frequently manifesting in infancy and childhood. The discovery of the underlying mutation in the survival of motor neurons 1 (SMN1) gene has accelerated preclinical research, leading to treatment targets and transgenic mouse models, but there is still no effective treatment. The clinical severity is inversely related to the copy number of SMN2, a modifying gene producing some full-length SMN transcript. Drugs shown to increase SMN2 function in vitro, therefore, have the potential to benefit patients with SMA. Because several drugs are now on the horizon of clinical investigation, we review recent clinical trials for SMA and discuss the challenges and opportunities associated with SMA drug development. Although an orphan disease, SMA is well-positioned for successful trials given that it has a common genetic etiology in most cases, that it can be readily diagnosed, that preclinical research in vitro and in transgenic animals has identified candidate compounds, and that trial networks have been established.
| S-EPMC4514700 | biostudies-other
Project description:Kennedy disease (KD, or spinal and bulbar muscular atrophy) is caused by a CAG/polyglutamine expansion in the androgen receptor (AR) gene. Both motoneurons and muscles are affected by KD, but where mutant ARs act to initiate this disease is not clear. We discuss recent insights into this disease with two main themes. (1) KD is androgen-dependent, suggesting that blocking androgen action may be an effective treatment. (2) Androgens may trigger KD by acting in muscles, which indirectly affects the motoneurons, suggesting that blocking AR function in muscles may rescue motoneurons from disease and provide an effective treatment. Future research will provide a better understanding of how androgens trigger KD and the relative contributions of motoneurons versus muscles in this disease.
| S-EPMC2603477 | biostudies-literature
Project description:ImportanceThe important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively).ObjectiveTo investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA.Design, setting, and participantsWe studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015.ExposuresWe used histochemical, biochemical, and molecular techniques to examine the muscle samples.Main outcomes and measuresRespiratory chain activity and mitochondrial content.ResultsResults of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P < .001), COX4 (26.6%; P < .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P < .001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P < .05).Conclusions and relevanceOur results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.
| S-EPMC4944827 | biostudies-literature
Project description:ObjectiveTo estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls.MethodsPeak aerobic capacity (VO2peak ) and workload (Wpeak ) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% Wpeak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near-infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X-ray absorptiometry assessed fat-free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (FatigueSME ) and six-minute walk test (Fatigue6MWT ), respectively.ResultsΔHHb-PEAK, ΔHHb-SME, VO2peak , Wpeak , FFM%, and 6MWT distance were lower (P < 0.001), and Fatigue6MWT and FatigueSME were higher (P < 0.001) in SMA compared to controls. ΔHHb-PEAK correlated with FFM% (r = 0.50) and VO2peak (r = 0.41) only in controls. Only in SMA, Fatigue6MWT was inversely correlated with Wpeak (r = -0.69), and FatigueSME was inversely correlated with FFM% (r = -0.55) and VO2peak (r = -0.69).InterpretationThis study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.
| S-EPMC8108417 | biostudies-literature