Survival Motor Neuron Research Articles

163P Real-World outcomes following onasemnogene abeparvovec in patients with SMA and One SMN2 gene copy: findings from the RESTORE Registry

163P Real-World outcomes following onasemnogene abeparvovec in patients with SMA and One SMN2 gene copy: findings from the RESTORE Registry

Evaluating the clinical efficacy of a long-read sequencing-based approach for carrier screening of spinal muscular atrophy

Spinal muscular atrophy (SMA) is the second most common fatal genetic disease in infancy. It is caused by deletion or intragenic pathogenic variants of the causative gene SMN1, which degenerates anterior horn motor neurons and leads to progressive myasthenia and muscle atrophy. Early treatment improves motor function and prognosis in patients with SMA, but drugs are expensive and do not cure the disease. Therefore, carrier screening seems to be the most effective way to prevent SMA birth defects. In this study, we genetically analyzed 1400 samples using multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), and compared the consistency of the results. We randomly selected 44 samples with consistent MLPA and qPCR results for comprehensive SMA analysis (CASMA) using a long-read sequencing (LRS)-based approach. CASMA results showed 100% consistency, visually and intuitively explained the inconsistency between exons 7 and 8 copy numbers detected by MLPA in 13 samples. A total of 16 samples showed inconsistent MLPA and qPCR results for SMN1 exon 7. CASMA was performed on all samples and the results were consistent with those of resampling for MLPA and qPCR detection. CASMA also detected an additional intragenic variant c.-39A>G in a sample with two copies of SMN1 (RT02). Finally, we detected 23 SMA carriers, with an estimated carrier rate of 1/61 in this cohort. In addition, CASMA identified the “2 + 0” carrier status of SMN1 and SMN2 in a family by analyzing the genotypes of only three samples (parents and one sibling). CASMA has great advantages over MLPA and qPCR assays, and could become a powerful technical support for large-scale screening of SMA.

Postnatal management of preterm infants with spinal muscular atrophy: experience from German newborn screening

BackgroundThe introduction of newborn screening (NBS) for spinal muscular atrophy (SMA) has increased the early diagnosis of 5q-associated SMA in presymptomatic and symptomatic preterm infants. National and international recommendations for treating preterms and newborns < 38 weeks of gestational age are unavailable. Our retrospective multicentre study aimed to evaluate the postnatal clinical course of preterm infants with 5q-associated SMA diagnosed since the implementation of NBS in Germany in 2021 and to summarize the German experience regarding the decision-making process for available treatment regimens for preterm infants with ≤ 3 survival of motor neuron 2 (SMN2) copies.ResultsTwelve preterm infants with 5q-associated SMA and a mean gestational age of 34.0 weeks (range: 26.1–36.8) and birth weight of 2022 g (range: 645–3370) were reported from 8/20 German SMA NBS follow-up centers using a pseudonymized questionnaire. Confirmatory diagnosis, including SMN2 copy number, was completed on average on postnatal day 13. All patients had a biallelic deletion of exon 7 or exons 7 and 8 of the survival of motor neuron 1 (SMN1) gene, with SMN2 copy numbers of two in 10 patients and three in two patients. The neonatal course was complicated by respiratory distress due to prematurity (n = 2), sepsis (n = 2), and jaundice (n = 2). At birth, 11 preterm infants (91.6%) were presymptomatic. However, the neurological status of one patient deteriorated at five weeks of age (postconceptional age of 41.8 weeks) prior to the start of treatment. Disease-modifying treatments were initiated in all patients at a mean postconceptional age of 38.8 weeks, with the majority receiving onasemnogene abeparvovec (83.3%, including 2 patients with prior risdiplam bridge therapy). Notably, consensus among participating experts from German neuromuscular centers resulted in 83.3% of patients receiving disease-modifying treatment at term.ConclusionsPremature infants with SMA require interdisciplinary care in close collaboration with the neuromuscular center. SMA NBS facilitates early initiation of disease-modifying therapy, ideally during the presymptomatic phase, which significantly influences the prognosis of the newborn.

An early Transcriptomic Investigation in Adult Patients with Spinal Muscular Atrophy Under Treatment with Nusinersen

Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre–mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted “restored” at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis.

Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

The spinal muscular atrophy gene product regulates actin dynamics.

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by low levels of the Survival of Motoneuron (SMN) protein. SMN interacts with and regulates the actin-binding protein profilin2a, thereby influencing actin dynamics. Dysfunctional actin dynamics caused by SMN loss disrupts neurite outgrowth, axonal pathfinding, and formation of functional synapses in neurons. Whether the SMN protein directly interacts with and regulates filamentous (F-) and monomeric globular (G-) actin is still elusive. In a quantitative single cell approach, we show that SMN loss leads to dysregulated F-/G-actin fractions. Furthermore, quantitative assessment of cell morphology suggests an F-actin organizational defect. Interestingly, this is mediated by an interaction of SMN with G- and F-actin. In co-immunoprecipitation, in-vitro pulldown and co-localization assays, we elucidated that this interaction is independent of the SMN-profilin2a interaction. Therefore, we suggest two populations being relevant for functional actin dynamics in healthy neurons: SMN-profilin2a-actin and SMN-actin. Additionally, those two populations may influence each other and therefore regulate binding of SMN to actin. In SMA, we showed a dysregulated co-localization pattern of SMN-actin which could only partially rescued by SMN restoration. However, dysregulation of F-/G-actin fractions was reduced by SMN restoration. Taken together, our results suggest a novel molecular function of SMN in binding to actin independent from SMN-profilin2a interaction.

Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.

Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human SMN1 gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of Drosophila SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.

Molecular mechanism of neurodegeneration in spinal muscular atrophy

In the last decade, pathogenetic methods for the treatment of spinal muscular atrophy 5q have been developed. These include increased expression of the SMN2 gene, correction of SMN2 splicing, or reexpression of the SMN1 gene. Despite the comprehension of the genetic causes of the disease and the existence of therapies, it is still not completely known which molecular mechanisms in SMN protein deficiency lead to the degeneration of motor neurons. Understanding the molecular pathways involved in the loss of motor neurons may help develop new therapeutic strategies. The article presents genetic and biochemical data that reveal the molecular mechanisms of neurodegeneration in spinal muscular atrophy 5q.

Abstract B083: The splicing factor SMNDC1 facilitates alternative RNA splicing, contributing to therapy resistance in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and lethal cancers, mainly due to its high resistance to existing treatments. The standard treatment for PDAC involves chemotherapy, either with Gemcitabine (GEM) combined with paclitaxel or the FOLFIRINOX regimen (5-fluorouracil (5FU), leucovorin, irinotecan, oxaliplatin). However, PDACs rapidly develop resistance to these therapies. Similar resistance is observed with new treatments targeting the KRAS-MAPK pathway, which is crucial in driving PDAC. Our preliminary studies have shown that Survival Motor Neuron Domain Containing 1 (SMNDC1) promotes PDAC tumor growth by facilitating exon retention, specifically cassette exon 4 (E4) of MAPK3, linking RNA splicing to KRAS-MAPK signaling. To uncover the mechanisms underlying PDAC therapeutic resistance, we have developed novel in vitro models of resistance to chemotherapy and MAPK inhibitors (MAPKi). Using these models, we found that SMNDC1 and MAPK3 E4 retention is significantly increased in GEM, 5FU (chemotherapy agents), Adagrasib, Sotorasib (KRAS inhibitors; KRASi G12C), and Selumetinib (MEK inhibitor; MEKi) resistant PDAC cells. Additionally, PDAC lines acutely treated (24h) with trametinib or selumetinib (MEKi) showed a doubling in the expression of SMNDC1 and MAPK3 E4 retention. Protein expression analysis via western blotting revealed that GEM, 5FU, Adagrasib, MRTX1133 (KRASi G12D), and Selumetinib resistant PDAC cells upregulated SMNDC1 expression compared to their sensitive counterparts. To determine the role of SMNDC1 in MAPK resistance, we tested SMNDC1 proficient and deficient PDAC cells with KRASi or MEKi. SMNDC1-deficient PDAC cells were more sensitive to these inhibitors than isogenic cells expressing SMNDC1. Furthermore, to show that increased E4 retention of MAPK3 drives resistance to KRASi or MEKi, we treated SMNDC1 proficient PDAC cells with these inhibitors and MAPK3 E4 specific antisense morpholino oligonucleotide (ASO), which increased sensitivity compared to cells treated with the inhibitor and control ASO. To determine if increased E4 retention is a resistance mechanism specific to therapies targeting upstream of ERK1, we treated PDAC cells, proficient and deficient in SMNDC1, with ERK inhibitors (MK8353, Temuterkib). No changes in sensitivity were observed, as these inhibitors target the ERK1 protein downstream of MAPK3 splicing. Additionally, in an orthogonal model, we found that mutant EGFR lung adenocarcinoma cells resistant to the third-generation tyrosine kinase EGFR inhibitor (Osimertinib) also had higher incorporation of E4 of MAPK3. This suggests that upstream inhibition of ERK in the MAPK pathway leads to increased MAPK3 E4 retention. These findings indicate that PDACs use a "splicing switch" to enhance ERK kinase activity, thereby resisting targeted therapies and chemotherapy in cancers driven by mutant KRAS-MAPK signaling pathways. Citation Format: Md Afjalus Siraj, Yushan Zhang, Deanne Yugawa, Gilbert Giri, Prabir Chakraborty, Grant Goda, Geeta Rao, Daniel Dominguez, Stefan Kubicek, Resham Bhattacharya, Luisa Escobar-Hoyos, Priyabrata Mukherjee. The splicing factor SMNDC1 facilitates alternative RNA splicing, contributing to therapy resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B083.

NURSING APPROACH IN SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy is an important genetic disease that affects motor neurons in the spine, causing muscle weakness, particularly in infancy. Spinal muscular atrophy occurs with a deletion of the survival motor neuron gene and is one of the leading causes of early death in infants. Although some drugs are used for the treatment of spinal muscular atrophy in the world and in Turkey, there is still no treatment method that provides complete recovery. The limited treatment options for spinal muscular atrophy, its inaccessibility and the poor prognosis of the disease negatively affect the quality of life of individuals and their families. All stages of the disease, starting from the diagnosis process, are very difficult for the patient and his family. A multidisciplinary approach is needed to help patients and their families cope with these difficulties. This approach includes areas such as medical care, rehabilitation, psychosocial support and education. It is essential that nurses, as key members of the health care team, improve the patient's quality of life, manage symptoms and support the individual and family in this process. In particular, supporting the patient and family in their care and educating them about their care needs is one of the most important roles of nurses. With this review, an attempt has been made to discuss the diagnostic methods, treatment process and nursing approaches of spinal muscular atrophy disease, which is a current problem in the world and in Turkey.

Characterization of SMA type II skeletal muscle from treated patients shows OXPHOS deficiency and denervation.

Spinal muscular atrophy (SMA) is a recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (survival of motor neuron 1). SMA is characterized by neuromuscular symptoms and muscle weakness. Several years ago, SMA treatment underwent a radical transformation, with the approval of 3 different SMN-dependent disease-modifying therapies. This includes 2 SMN2 splicing therapies - risdiplam and nusinersen. One main challenge for type II SMA patients treated with these drugs is ongoing muscle fatigue, limited mobility, and other skeletal problems. To date, few molecular studies have been conducted on SMA patient-derived tissues after treatment, limiting our understanding of what targets remain unchanged after the spinal cord-targeted therapies are applied. Therefore, we collected paravertebral muscle from 8 type II patients undergoing spinal surgery for scoliosis and 7 controls. We used RNA-seq to characterize their transcriptional profiles and correlate these molecular changes with muscle histology. Despite the limited cohort size and heterogeneity, we observed a consistent loss of oxidative phosphorylation (OXPHOS) machinery of the mitochondria, a decrease in mitochondrial DNA copy number, and a correlation between signals of cellular stress, denervation, and increased fibrosis. This work provides new putative targets for combination therapies for type II SMA.

Application of CNVPLUS-array custom microarray in genetic analysis of spinal muscular atrophy

To assess the application value of CNVPLUS-array for the genetic analysis of Spinal muscular atrophy (SMA). From June 2021 to December 2022, CNVPLUS-array technique was employed to test the SMN1 and SMN2 genes among peripheral blood samples from 17 suspected SMA patients, 18 core families with suspected SMA, and 25 healthy individuals. The results were compared with those of multiple ligation-dependent probe amplification (MLPA) assay. Samples with inconsistent results were subjected to nested PCR or comprehensive analysis of SMA. CNVPLUS-array has identified 35 SMA patients, 36 carriers, and 25 healthy individuals. In comparison, MLPA has identified 34 SMA patients, 36 carriers, and 26 healthy individuals. The two methods demonstrated a high consistency (Kappa = 0.968, P < 0.001). Additionally, CNVPLUS-array has identified one patient with compound heterozygous variants of SMN1 and one carrier with a [2+0] genotype. CNVPLUS-array not only can accurately determine the copy numbers of SMN1 and SMN2 genes, but also identify point mutations in SMN1 and [2+0] carriers, which has offered a new method for the genetic testing of SMA.

Sensory dysfunction in SMA type 2 and 3 - adaptive mechanism or concomitant target of damage?

BackgroundThe motor neuron survival protein performs numerous cellular functions; hence, spinal muscular atrophy (SMA) is considered to be a multi-organ disease with possible sensory system damage. The controversy surrounding the presence of sensory disturbances, prompted us to conduct standard electrophysiological studies and assess the sensory thresholds for different modalities in adults with SMA types 2 and 3. The study group consisted of 44 adult SMA patients (types 2 and 3). All patients underwent neurological examination using the Hammersmith Functional Motor Scale – Expanded (HFMSE). Standard sensory electrophysiological studies in the ulnar nerve and the estimation of vibratory, temperature, and warm- and cold-induced pain thresholds with temperature dispersion assessment were performed using quantitative sensory testing (QST).ResultsThe most repeatable result was the high amplitude of the sensory nerve action potentials (SNAP) in SMA patients compared to controls. This was higher in type 2 patients compared to type 3a and 3b patients and patients with low HFSME scores. Patients with SMA, especially type 3b presented a longer sensory latency and slower conduction velocity than did controls. Cold pain threshold was higher and warm dispersion larger in SMA. The vibratory limit was higher in patients with high HFSME scores.ConclusionsA high SNAP amplitude suggests sensory fibre hyperactivity, which may be based on overactivation of metabolic pathways as an adaptive mechanism in response to SMN protein deficiency with additionally coexisting small C- and A-delta fibre damage. SMA patients seem to have a concomitant, mild demyelinating process present at the early SMA stage.

Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1-3.

Biomarkers can be used to assess the severity of spinal muscular atrophy (5q SMA; SMA). Despite their potential, the relationship between biomarkers and clinical outcomes in SMA remains underexplored. This study aimed to assess the association among biomarkers, phenotypes, and motor milestones in Chinese patients diagnosed with SMA. We collected retrospective clinical and follow-up data of disease-modifying therapy (DMT)-naïve patients with SMA at our center from 2019 to 2021. Four biomarkers were included: survival motor neuron 2 (SMN2) copies, neuronal apoptosis inhibitory protein (NAIP) copies, full-length SMN2 (fl-SMN2), and F-actin bundling protein plastin 3 (PLS3) transcript levels. Data were analyzed and stratified according to SMA subtype. Of the 123 patients, 30 were diagnosed with Type 1 (24.3%), 56 with Type 2 (45.5%), and 37 with Type 3 (30.1%). The mortality rate for Type 1 was 50%, with median survival times of 2 and 8 months for types 1a and 1b, respectively. All four biomarkers were correlated with disease severity. Notably, fl-SMN2 transcript levels increased with SMN2 copies and were higher in Type 2b than those in Type 2a (p = 0.028). Motor milestone deterioration was correlated with SMN2 copies, NAIP copies, and fl-SMN2 levels, while PLS3 levels were correlated with standing and walking function. Our findings suggest that SMN2 copies contribute to survival and that fl-SMN2 may serve as a valuable biomarker for phenotypic variability in SMA Type 2 subtypes. These insights can guide future research and clinical management of SMA.

Abnormal expression of myosin heavy chains in early postnatal stages of spinal muscular atrophy type I at single fibre level.

We investigated myosin heavy chain (MyHC) isoform expression at early postnatal stages of clinically and genetically confirmed spinal muscular atrophy type 1 (SMA1) patients, in order to study the muscle fibre differentiation compared to age-matched controls at single fibre level. Open skeletal muscle biopsies were performed from the quadriceps muscle in four SMA1 patients and three age-matched controls. Standard techniques were used for immunohistochemistry of embryonic and foetal MyHCs. Type I, IIa and IIx MyHCs were assessed by applying quadruple immunofluorescence. Western blot was performed to analyse the amount of survival motor neuron (SMN) protein in the muscle samples. There were profound and early alterations in MyHC expression from 7 days of life compared to age-matched controls. The expression of type IIx MyHC was completely lost in SMA1 and instead developmental isoforms remained highly expressed. Foetal MyHC was still, at 3.5 months of age, expressed in the majority of muscle fibres in SMA1 patients, whereas it was completely downregulated in age-matched controls. The level of SMN protein was reduced in all SMN1 patients. The abnormal pattern of MyHC expression in postnatal stages of SMA1 was observed early in the newborn period, which may have implications for the effects of gene therapy, since there are clear clinical benefits from early treatment. Whether such aberrant and delayed expression of MyHCs can be completely restored by postnatal gene therapy remains to be studied and may also have implications for new phenotypes that will evolve with new therapies.

The functional state of the respiratory system of the patients with proximal spinal muscular atrophy 5q (SMA 5q): from the natural history of the disease to the era of pathogenetic therapy. Problems and expectations

Proximal spinal muscular atrophy 5q is an autosomal recessive neuromuscular disease. This disorder is characterized by progressive symptoms of flaccid paralysis and muscular atrophy due to degeneration of α-motor neurons in the anterior horns of the spinal cord. The disease is caused by the lack of a fully functional SMN protein due to homozygous deletion of exon 7 in the SMN1 gene. For a long time, spinal muscular atrophy was the leading genetic cause of infant mortality. With the introduction of modern pathogenetic treatment methods that modify the disease, the duration and quality of life of patients increases, and a “blurring of boundaries” between types of spinal muscular atrophy and the formation of new phenotypes happens. In this regard, approaches to patient management, including approaches to the assessment and correction of respiratory disorders, are changing. The review of the available medical literature was conducted. The clinical studies on spinal muscular atrophy in the natural course of the disease and with the use of pathogenetic drugs were analyzed, as well as the data on the state of the respiratory system of the patients.

Unraveling innovative treatments for spinal muscular atrophy: a brief review

In the past few years, there have been amazing breakthroughs in treating spinal muscular atrophy (SMA), which is a big deal considering it's been studied for over a hundred years. Now, there are three approved therapies that all work to increase SMN protein production. They do this by fixing the genetic problem either by replacing the faulty SMN1 gene or by helping the SMN2 gene produce more of the right kind of protein. One way they do this is by using a special virus called adeno- associated viral vectors (AAV9) to deliver the gene therapy because the SMN1 gene is small enough to fit inside. The paper discusses the evolution of SMA treatment, focusing on advancements like gene therapy and new drug treatments. It highlights challenges in interpreting efficacy, especially regarding disease classification. Despite successes, issues like limited trial populations and varying disease stages pose complexities in care. With expanding treatment options, including those in advanced development stages, the landscape of SMA management grows more intricate. However, the importance of timely diagnosis and interdisciplinary clinical management remains crucial, recognizing that despite drug treatments, many patients still face significant disease burdens. This article aims to give a quick rundown of spinal muscular atrophy, starting from when people first noticed the disease up until now, when there are some really cool new treatments that are changing how the disease affects people.

Outcomes for patients in the RESTORE registry with spinal muscular atrophy and four or more SMN2 gene copies treated with onasemnogene abeparvovec

ObjectiveWe describe outcomes following onasemnogene abeparvovec monotherapy for patients with ≥four survival motor neuron 2 (SMN2) gene copies in RESTORE, a noninterventional spinal muscular atrophy patient registry. MethodsWe evaluated baseline characteristics, motor milestone achievement, post-treatment motor function, use of ventilatory/nutritional support, and adverse events as of December 22, 2022. ResultsAt data cutoff, 19 patients in RESTORE had ≥four SMN2 copies and were treated with onasemnogene abeparvovec monotherapy (n=12 [63.2%] four copies; n=7 [36.8%] >four copies). All patients were identified by newborn screening and were reported as asymptomatic at diagnosis. Median age at onasemnogene abeparvovec administration was 3.0 months. Median time from treatment to last recorded visit was 15.4 months, with a range of post-treatment follow-up of 0.03–39.4 months. All 12 children who were assessed for motor development achieved new milestones, including standing alone (n=2) and walking alone (n=5). Five children reported one or more treatment-emergent adverse events (one Grade 3 or greater). No deaths or use of ventilatory/nutritional support were reported. ConclusionsReal-world findings from the RESTORE registry indicate that patients with ≥four SMN2 gene copies treated with onasemnogene abeparvovec monotherapy demonstrated improvements in motor function. Adverse events experienced by these patients were consistent with previously reported findings.

The systemic complexity of a monogenic disease: the molecular network of spinal muscular atrophy.

Monogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal Muscular Atrophy (SMA) is one such monogenic model caused by mutation or deletion of the Survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow to identify critical disease-driving molecules. Here, we analyzed the systemic characteristics of SMA employing proteomics, phosphoproteomics, translatomics and interactomics from two mouse models with different disease-severities and genetics. This systems approach revealed sub-networks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases.

Current Treatment Process and Challenges for Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) presents as a pediatric neuromuscular disorder resulting from mutations in the survival motor neuron 1(SMN1) gene, with an incidence of approximately 10-13 per 100,000 live births. This condition manifests primarily through muscle weakness and atrophy, particularly affecting the proximal limb muscles. A homozygous deletion of exon 7 in the SMN1 gene is the most common genetic mutation in SMA and serves as a sensitive diagnostic marker. This article comprehensively explores various aspects of SMA, including its types, diagnostic methods, and management strategies. Pulmonary care, gastrointestinal (GI) management, nutritional supplementation, orthopedic spinal care, and physiotherapy play crucial roles in delaying disease progression. Current pharmacological treatments for SMA are diverse and evolving. Notable among them is Zolgensma (formerly AVXS-101 or Onasemnogene abeparvovec), a gene replacement therapy utilizing an adeno-associated virus vector to boost functional SMN protein levels. Sodium vanadate, a phosphatase inhibitor, and risdiplam (RO703406) are agents that modulate SMN2 splicing to augment the production of functional SMN protein. Riluzole acts as a neuroprotective agent by preventing SMN deficiency, while reldesemtive (CK-2127107) is under development as a muscle-enhancing therapy to ameliorate skeletal muscle function during fatigue. While pharmacological therapies for SMA are advancing, a holistic approach involving comprehensive multidisciplinary care, encompassing pulmonary support, proper nutritional supplementation, and adept orthopedic management, significantly contributes to the effective management of SMA.