[Clinical efficacy of nusinersen sodium in the treatment of children with spinal muscular atrophy]. / è¯ºè¥¿é‚£ç”Ÿé’ æ²»ç–—è„Šé«“æ€§è‚ŒèŽç¼©ç—‡å„¿ç«¥çš„ä¸´åºŠåˆ†æž.

OBJECTIVES: To investigate the efficacy and safety of nusinersen sodium in the treatment of children with spinal muscular atrophy (SMA). METHODS: A retrospective analysis was conducted on the clinical data of 50 children with 5q SMA who received nusinersen sodium treatment and multidisciplinary treatment management in Shanxi Children's Hospital from February 2022 to February 2024. RESULTS: Compared with the baseline data, 67% (8/12), 74% (35/47), and 74% (35/47) of the SMA children had a clinically significant improvement in the scores of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module, respectively, and the distance of 6-minute walking test increased from 207.00 (179.00, 281.50) meters to 233.00 (205.25, 287.50) meters (P<0.05) after nusinersen sodium treatment. Of all 50 children with SMA, 24 (48%) showed good tolerability after administration, with no significant or persistent abnormalities observed in 2 034 laboratory test results, and furthermore, there were no serious or immunological adverse events related to the treatment. After treatment, there was a significant change in forced vital capacity as a percentage of the predicted value in 27 children with restrictive ventilatory dysfunction, as well as a significant change in the level of 25-(OH) vitamin D in 15 children with vitamin D deficiency (P<0.05). CONCLUSIONS: For children with SMA, treatment with nusinersen sodium can continuously improve the response rates of motor function scales, with good tolerability and safety.

A horizontal and perpendicular interlaminar approach for intrathecal nusinersen injection in patients with spinal muscular atrophy and scoliosis: an observational study.

BACKGROUND: Lumbar puncture is challenging for patients with scoliosis. Previous ultrasound-assisted techniques for lumbar puncture used the angle of the probe as the needle trajectory; however, reproducing the angle is difficult and increases the number of needle manipulations. In response, we developed a technique that eliminated both the craniocaudal and lateromedial angulation of the needle trajectory to overall improve this technique. We assessed the feasibility and safety of this method in patients with scoliosis and identify factors related to difficult lumbar puncture. METHODS: Patients with spinal muscular atrophy and scoliosis who were referred to the anesthesia department for intrathecal nusinersen administrations were included. With a novel approach that utilized patient position and geometry, lumbar puncture was performed under ultrasound guidance. Success rates, performance times and adverse events were recorded. Clinical-demographic and spinal radiographic data pertaining to difficult procedures were analyzed. RESULTS: Success was achieved in all 260 (100%) lumbar punctures for 44 patients, with first pass and first attempt success rates of 70% (183/260) and 87% (226/260), respectively. Adverse events were infrequent and benign. Higher BMI, greater skin dural sac depth and smaller interlaminar size might be associated with greater difficulty in lumbar puncture. CONCLUSIONS: The novel ultrasound-assisted horizontal and perpendicular interlaminar needle trajectory approach is an effective and safe method for lumbar puncture in patients with spinal deformities. This method can be reliably performed at the bedside and avoids other more typical and complex imaging such as computed tomography guided procedure.

Safety analysis of laboratory parameters in paediatric patients with spinal muscular atrophy treated with nusinersen.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder that can be treated with intrathecal nusinersen, an antisense oligonucleotide. In addition to efficacy, safety is a determining factor in the success of any therapy. Here, we aim to assess the safety of nusinersen therapy in paediatric patients with SMA. METHODS: Laboratory data of paediatric patients with SMA who received nusinersen between October 2019 and May 2022 were retrospectively analysed. RESULTS: During the observation period, 46 infants and children aged 2.9 months to 13.6 years received a total of 213 nusinersen doses without safety concerns. Inflammatory markers were stable throughout the study. International normalized ratio was increased by 0.09 per injection. Urea levels were increased by 0.108 mmol/L, and cystatin C decreased by 0.029 mg/L per injection. There were no significant changes in platelet count, activated partial thrombin time, creatinine levels or liver enzyme levels during treatment. The cerebrospinal fluid (CSF) leukocyte count remained stable, and total protein increased by 24.038 mg/L per injection. CONCLUSION: Our data showed that nusinersen therapy is generally safe in children with SMA. Laboratory monitoring did not identify any persistent or significantly abnormal findings. CSF protein should be monitored to gain more insights.

Analysis of the efficacy and adverse effects of nusinersen in the treatment of children with spinal muscular atrophy in China.

OBJECTIVE: This study was based on a retrospective clinical observational cohort study of a two-center application of nusinersen in China to evaluate the clinical efficacy and adverse effects of nusinersen in the treatment of SMA (spinal muscular atrophy) Types 1-3. METHODS: Clinical data from children with clinically and genetically confirmed 5qSMA from a double center in western China (the Second Affiliated Hospital of Xi'an Jiaotong University and the Second Hospital of West China of Sichuan University). All children were younger than 18 years of age. Patients were assessed for motor function and underwent blood and fluid tests before each nusinersen injection. RESULTS: At 14-month follow-up, 100% of children had improved their HFMSE (Hammersmith Functional Motor Scale Expanded) score, 83.6% had improved their CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) score, and 66.6% had improved their RULM (Revised Upper Limb Module) score by ≥3 points from baseline, and their 6MWT (6-min walk test) was 216.00 ± 52.08 m longer than at baseline. The age of the child at the start of treatment was negatively correlated with the clinical efficacy of nusinersen; the younger the child, the better the response to treatment. No significant adverse effects affecting the treatment and quality of life of the child were observed during the treatment of SMA with nusinersen. CONCLUSION: This study concluded that nusinersen is clinically beneficial for children with SMA in western China, with mild adverse effects.

Unveiling the adverse events of Nusinersen in spinal muscular atrophy management based on FAERS database.

This study aims to collect and analyze adverse event (AE) reports related to Nusinersen from the FAERS database. The study employed a combination of signal quantification techniques, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), to enhance the accuracy of signal detection and reduce the risk of false positives or negatives. Between the first quarter of 2017 and the third quarter of 2023, the FAERS database collected a total of 11,485,105 drug AE reports, of which 5772 were related to Nusinersen. Through signal mining analysis, 218 preferred term (PT) signals involving 27 system organ classes (SOCs) were identified. The study discovered AEs related to metabolism and nutrition disorders, psychiatric disorders, and cardiac disorders SOCs, which were not mentioned in the product information. Additionally, complications directly related to the intrathecal administration of Nusinersen, such as increased CSF pressure, positive CSF red blood cell count, and AEs related to the method of drug use, such as neuromuscular scoliosis and cerebrospinal fluid reservoir placement, were highlighted. Notably, AEs related to renal function abnormalities, such as abnormal Urine protein/creatinine ratio and protein urine presence, showed higher frequency and signal strength. The findings of this study emphasize the importance of comprehensive safety monitoring in the clinical application of Nusinersen. These results are significant for guiding future clinical practices, improving disease management strategies, and developing safer treatment protocols.

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1. Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood-brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.

Study of nusinersen metabolites in the cerebrospinal fluid of children with spinal muscular atrophy using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

The study aimed to analyze nusinersen metabolites in the cerebrospinal fluid samples using ion-pair reversed-phase ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Three different sample preparation methods were tested for extraction and purification, but solid phase extraction appeared to be the most suitable, allowing a significant sample enrichment (40-fold). This step was necessary to detect and identify metabolites of nusinersen in the cerebrospinal fluid. The developed and applied analytical procedure enabled the identification of nusinersen metabolites: sequences shorter by several nucleotides from the 3' end; shorter by several nucleotides from both the 3' and 5' ends; and some depurination products. To the best of our knowledge, this is the first report on the analysis and identification of nusinersen metabolites in cerebrospinal fluid samples taken from children with spinal muscular atrophy treated with Spinraza.

An updated systematic review on spinal muscular atrophy patients treated with nusinersen, onasemnogene abeparvovec (at least 24 months), risdiplam (at least 12 months) or combination therapies.

OBJECTIVE: This systematic review provides an update on outcomes for patients with spinal muscular atrophy (SMA) type 1 to 4 treated with approved therapeutics, including the most recent, risdiplam, for an observation period of up to 48 months. METHODS: A systematic literature search was conducted in July 2023 in four databases. Selected publications were assessed for internal validity and risk of bias by two authors and relevant data were extracted into standardised tables. Results were summarised narratively as substantial heterogeneity of studies prevents meaningful quantitative analysis. RESULTS: Twenty observational studies and one RCT were included in the analysis, fifteen studies on nusinersen, one on onasemnogene abeparvovec and two on risdiplam. Evidence supports the effectiveness of the therapies in motor function improvement for up to 48 months of follow-up in the SMA types specified in their respective indications. Better results were observed with earlier treatment initiation and higher baseline function. Whilst motor improvement was consistently observed, regardless of SMA type or treatment used, we noted no significant improvements in respiratory and nutritional outcomes. Quality of life endpoints were rarely investigated. Adverse events were common but seldom classified as treatment-related except for post-lumbar puncture syndrome, which was frequently reported across nusinersen studies. CONCLUSION: The treatment of SMA with the new therapies changes the disease phenotype with changes in motor function far exceeding any improvement in respiratory and nutritional function. Questions persist on long-term efficacy, potential regressions, impact on quality of life and social functioning, therapy duration, and discontinuation indicators.

Impact of Spinal Surgery on Intrathecal Nusinersen Injections in Pediatric Spinal Muscular Atrophy.

BACKGROUND: Complex spinal deformities necessitate surgical interventions that may intervene with intrathecal injections in patients with spinal muscular atrophy (SMA). This study aimed to determine the effect of spinal deformity correction surgery on nusinersen administration. METHODS: Pediatric patients with SMA, operated by a single surgeon, either via magnetically controlled growing rod (MCGR) or definitive fusion (DF) with skip instrumentation, were evaluated retrospectively in terms of safety and feasibility of intrathecal injections. Patients' and their parents' perspectives were evaluated through a questionnaire regarding any shift in the setting of injections. RESULTS: Fourteen patients with 15 spinal surgeries (10 MCGR and 5 DF) were included. Eleven patients received intrathecal treatment both before and after the surgery. Preoperative (n=3) and postoperative (n=9) fluoroscopic guidance was required leading to a shift in the application settings in 6 patients. Of 106 preoperative injections, 15% required fluoroscopy and 2% required anesthesia. Postoperatively, of 88 injections, 73% required fluoroscopy and 26% required anesthesia. No patients discontinued intrathecal injections due to technical difficulties associated with the spinal surgery. CONCLUSIONS: This study demonstrates that spinal surgery does not prevent safe and successful intrathecal nusinersen injections. In the DF group, the skip instrumentation technique provided access to interlaminal space for intrathecal injections. In either surgical group, no further auxillary approach was required. Modifications in the injection technique require an institutional approach, and concerns of patients and their families should be addressed accordingly. LEVEL OF EVIDENCE: IV.

Improvement in functional motor scores in patients with non-ambulatory spinal muscle atrophy during Nusinersen treatment in South Korea: a single center study.

We analyzed the changes in various motor function scores over a four-year period in patients with non-ambulatory spinal muscular atrophy (SMA) during Nusinersen treatment. Patients underwent Hammersmith Infant Neurological Examination (HINE) or Hammersmith Functional Motor Scale Expanded (HFMSE) before treatment, and approximately every 4 months thereafter. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) or Children's Hospital of Philadelphia - Adult Test of Neuromuscular Disorders (CHOP ATEND), Revised Upper Limb Module (RULM), and Motor Function Measure (MFM) were performed based on baseline functional status. Narrative interviews were conducted to explore post-treatment physical improvement regarding activities of daily living (ADLs) and fatigue after ADLs. Based on HFMSE results, 9 patients achieved minimum clinically important differences. Average rates of change (slopes) with corresponding 95% confidence intervals for all assessment tools were in a positive direction. CHOP-INTEND showed the most prominent improvement in children and adolescents followed by HFMSE. Improvements in CHOP-ATEND were most noticeable in adults. Improvements were accompanied by changes in ADLs as observed in the narrative interviews. It is necessary to consider various functional aspects to determine the effectiveness of Nusinersen therapy. The objective assessment of the therapeutic effect of Nusinersen in non-ambulatory SMA requires consideration of functional aspects and the related ADLs.

Treatment Options in Spinal Muscular Atrophy: A Pragmatic Approach for Clinicians.

Spinal muscular atrophy (SMA) is a rare neurodegenerative neuromuscular disorder with a wide phenotypic spectrum of severity. SMA was previously life limiting for patients with the most severe phenotype and resulted in progressive disability for those with less severe phenotypes. This has changed dramatically in the past few years with the approvals of three disease-modifying treatments. We review the evidence supporting the use of currently approved SMA treatments (nusinersen, onasemnogene abeparvovec, and risdiplam), focusing on mechanisms of action, side effect profiles, published clinical trial data, health economics, and pending questions. Whilst there is robust data from clinical trials of efficacy and side effect profile for individual drugs in select SMA populations, there are no comparative head-to-head clinical trials. This presents a challenge for clinicians who need to make recommendations on the best treatment option for an individual patient and we hope to provide a pragmatic approach for clinicians across each SMA profile based on current evidence.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China. METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit. RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses. CONCLUSION: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04419233.

Adherence and Persistence Among Risdiplam-Treated Individuals with Spinal Muscular Atrophy: A Retrospective Claims Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions and/or mutations in the survival of motor neuron 1 (SMN1) gene. Risdiplam, the first and only oral SMN2 pre-mRNA splicing modifier, is US Food and Drug Administration-approved for the treatment of pediatric and adult patients with SMA. For patients with SMA, long-term adherence to and persistence with an SMA treatment may be important for achieving maximum clinical benefits. However, real-world evidence on patient adherence to and persistence with risdiplam is limited. METHODS: This retrospective study examined real-world adherence and persistence with risdiplam from a specialty pharmacy in patients with SMA over a 12-month period. Adherence was estimated by using proportion of days covered (PDC) and was calculated over variable (time between first and last fill) and fixed (time from first fill to study period end) intervals. Persistence was defined as no gap in supply ≥ 90 days. Patients were included if the time between the index date and study observation period was ≥ 12 months, if they initiated risdiplam between August 2020 and September 2022, received ≥ 2 risdiplam fills, and had an SMA diagnosis associated with a risdiplam fill. Subgroup analyses of risdiplam adherence and persistence were performed by age and primary payer type. RESULTS: The proportion of patients (N = 1636) adherent at 12 months based on variable and fixed interval PDC was 93% and 79%, respectively. Adherence was high among patients on commercial insurance, Medicaid, or Medicare (range 86-96%). Mean persistence was 330.4 days. The highest proportion of patients who were persistent were on Medicaid (81%). CONCLUSION: These findings demonstrate that patient adherence to and persistence with risdiplam treatment were high, including across all subgroups tested.

Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment.

5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients. Here we have longitudinally investigated SMA and nusinersen effects on local immune responses in the cerebrospinal fluid (CSF) - a surrogate of central nervous system parenchyma. Single-cell transcriptomics (SMA: N = 9 versus Control: N = 9) reveal NK cell and CD8+ T cell expansions in untreated SMA CSF, exhibiting activation and degranulation markers. Spatial transcriptomics coupled with multiplex immunohistochemistry elucidate cytotoxicity near chromatolytic motoneurons (N = 4). Post-nusinersen treatment, CSF shows unaltered protein/transcriptional profiles. These findings underscore cytotoxicity's role in SMA pathogenesis and propose it as a therapeutic target. Our study illuminates cell-mediated cytotoxicity as shared features across motoneuron diseases, suggesting broader implications.

Efficient systemic CNS delivery of a therapeutic antisense oligonucleotide with a blood-brain barrier-penetrating ApoE-derived peptide.

Antisense oligonucleotide (ASO) has emerged as a promising therapeutic approach for treating central nervous system (CNS) disorders by modulating gene expression with high selectivity and specificity. However, the poor permeability of ASO across the blood-brain barrier (BBB) diminishes its therapeutic success. Here, we designed and synthesized a series of BBB-penetrating peptides (BPP) derived from either the receptor-binding domain of apolipoprotein E (ApoE) or a transferrin receptor-binding peptide (THR). The BPPs were conjugated to phosphorodiamidate morpholino oligomers (PMO) that are chemically analogous to the 2'-O-(2-methoxyethyl) (MOE)-modified ASO approved by the FDA for treating spinal muscular atrophy (SMA). The BPP-PMO conjugates significantly increased the level of full-length SMN2 in the patient-derived SMA fibroblasts in a concentration-dependent manner with minimal to no toxicity. Furthermore, the systemic administration of the most potent BPP-PMO conjugates significantly increased the expression of full-length SMN2 in the brain and spinal cord of SMN2 transgenic adult mice. Notably, BPP8-PMO conjugate showed a 1.25-fold increase in the expression of full-length functional SMN2 in the brain. Fluorescence imaging studies confirmed that 78% of the fluorescently (Cy7)-labelled BPP8-PMO reached brain parenchyma, with 11% uptake in neuronal cells. Additionally, the BPP-PMO conjugates containing retro-inverso (RI) D-BPPs were found to possess extended half-lives compared to their L-counterparts, indicating increased stability against protease degradation while preserving the bioactivity. This delivery platform based on BPP enhances the CNS bioavailability of PMO targeting the SMN2 gene, paving the way for the development of systemically administered neurotherapeutics for CNS disorders.

Cost-Effectiveness of Technologies for the Treatment of Spinal Muscular Atrophy: A Systematic Review of Economic Studies.

OBJECTIVES: This study aims to systematically collect data on cost-effectiveness analyses that assess technologies to treat type I and II spinal muscular atrophy and evaluate their recommendations. METHODS: A structured electronic search was conducted in 4 databases. Additionally, a complementary manual search was conducted. Complete economic studies that evaluated nusinersen, risdiplam, onasemnogene abeparvovec (OA), and the best support therapy (BST) from the health system's perspective were selected. The incremental cost-effectiveness ratios were compared with various thresholds for the analysis. The review was registered a priori in PROSPERO (CRD42022365391). RESULTS: Twenty studies were included in the analyses. They were all published between 2017 and 2022 and represent the recommendations in 8 countries. Most studies adopted 5, 6, or 10-state Markov models. Some authors took part in multiple studies. Four technologies were evaluated: BST (N = 14), nusinersen (N = 19), risdiplam (N = 5), and OA (N = 9). OA, risdiplam, and nusinersen were considered inefficient compared with the BST. Risdiplam and OA were generally regarded as cost-effective when compared with nusinersen. Because nusinersen is not a cost-effective drug, no recommendation can be derived from this result. Risdiplam and OA were compared in 2 studies that presented opposite results. CONCLUSIONS: Nusinersen, risdiplam, and OA are being adopted worldwide as a treatment for spinal muscular atrophy. Despite that, the pharmacoeconomic analyses show that the technologies are not cost-effective compared with the BST. The lack of controlled studies for risdiplam and OA hamper any conclusions about their face-to-face comparison.

Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its anti-SMA role remains unclear. OBJECTIVE: This study aims to reveal the anti-SMA mechanisms of securinine. METHODS: Securinine-associated targets were acquired from Herbal Ingredients' Targets (HIT), Similarity Ensemble Approach (SEA), and SuperPred. SMA-associated targets were obtained from GeneCards and Dis- GeNET. Protein-protein Interaction (PPI) network was constructed using GeneMANIA, and hug targets were screened using cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfifiler. Molecular docking was conducted using Pymol and Auto- Dock. In vitro assays were used to verify the anti-SMA effects of securinine. RESULTS: Twenty-six intersection targets of securinine and SMA were obtained. HDAC1, HDAC2, TOP2A, PIK3R1, PRMT5, JAK2, HSP90AB1, TERT, PTGS2, and PAX8 were the core targets in PPI network. GO analysis demonstrated that the intersecting targets were implicated in the regulation of proteins, steroid hormones, histone deacetylases, and DNA transcription. KEGG analysis, pathway-pathway, and hub target-pathway networks revealed that securinine might treat SMA through TNF, JAK-STAT, Ras, and PI3K-Akt pathways. Securinine had a favorable binding affinity with HDAC1, HSP90AB, JAK2, PRMT5, PTGS2, and TERT. Securinine rescued viability suppression, mitochondria damage, and SMN loss in the SMA cell model. Furthermore, securinine increased HDAC1 and PRMT5 expression, decreased PTGS2 expression, suppressed the JAK2-STAT3 pathway, and promoted the PI3K-Akt pathway. CONCLUSION: Securinine might alleviate SMA by elevating HDAC1 and PRMT5 expression and reducing PTGS2 via JAK2-STAT3 suppression and PI3K-Akt activation.

[Risdiplam for the treatment of spinal muscular atrophy]. / Risdiplam pri lechenii spinal'noi myshechnoi atrofii.

Spinal muscular atrophy (SMA) is a devastating disease that is the leading genetic cause of death in infants and young children. It includes a broad spectrum of phenotypes that are classified into clinical groups based on the age of onset and maximum motor function achieved. The most common form of SMA is due to a defect in the survival motor neuron 1 gene (SMN1) localized to 5q11.2-q13.3. The development of clinical symptoms and disease progression is thought to be due to decreased levels of survival motor neuron (SMN) protein. SMA type 1 results in almost inevitable mortality within the first 2 years of life. The first two drugs approved globally for the treatment of SMA were the antisense oligonucleotide nusinersen (Spinraza), and the gene therapy onasemnogene abeparvovec-xioi (Zolgensma). Both interventions have approval and restrictions on use in different countries around the world. Despite these approved therapies, the medical unmet need in SMA (the majority of patients with SMA are not on a disease-modifying therapy) remains high with therapies in the pipeline to address some of the remaining limitations. The third and more recently approved drug for SMA is risdiplam (Evrysdi), an orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing toward the production of full-length SMN2 mRNA to increase functional SMN protein levels. In Russia the drug risdiplam was approved for use on November 26, 2020 with indications for the treatment of SMA in patients aged 2 months and older, and in 2023 the indications were expanded - use is allowed starting from the birth. Risdiplam is widely distributed into the CNS and peripheral tissues including muscles. Following risdiplam administration, SMN protein levels compared with baseline levels increase between 2- and 6-fold depending on the SMA phenotype treated. The risdiplam clinical development program currently has four ongoing clinical trials assessing its safety and efficacy. Clinical trials included more than 450 patients receiving risdiplam to date, has been well tolerated and no treatment-related safety findings leading to study withdrawal have been observed. Data from real clinical practice - more than 11.000 patients worldwide receive therapy with risdiplam, also confirm the safety and good tolerability of the drug.