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.

[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.

Treatment of Symptomatic Spinal Muscular Atrophy with Nusinersen: A Prospective Longitudinal Study on Scoliosis Progression.

Background: Nusinersen treatment has demonstrated efficacy in improving clinical outcomes for spinal muscular atrophy (SMA), yet its impact on scoliosis progression remains unclear. Objective: This study aimed to assess the progression of scoliosis in pediatric patients with SMA undergoing nusinersen treatment. Methods: In this prospective study, data were systematically collected from Hong Kong pediatric SMA patients receiving nusinersen between 2018 and 2023. All patients had longitudinal radiographic studies pre-nusinersen, and at half-yearly or yearly intervals during treatment based on the scoliosis severity. Motor function evaluations were conducted pre-nusinersen, and after starting treatment at 6- and 12-month intervals. Results: Twenty-three patients ((SMA type 1 (SMA1) = 8, SMA type 2 (SMA2) = 7, SMA type 3 (SMA3) = 8)) with a median age of 5.8 years (range: 0.4-17.5 years) at nusinersen initiation, and median follow-up duration of 3.4 years (range: 1.1-5.2 years) were included. During the study period, motor scores remained stable or improved in 83% of patients. However, scoliosis progressed across all subtypes, with mean annual progression rates of 5.2, 11.9, and 3.6 degrees in SMA1, SMA2, and SMA3 respectively. Patients initiating nusinersen between ages 5 and 11 years exhibited the most rapid progression, with rates of 11.8, 16.5, and 7.3 degrees per year in SMA1, SMA2, and SMA3 respectively. Positive correlations were observed between the difference in CHOP-INTEND score post-nusinersen and scoliosis progression in SMA1 (rs = 0.741, p = 0.041). Conversely, negative correlations were found between the difference in HFMSE score post-nusinersen and scoliosis progression in SMA2 (rs =-0.890, p = 0.012) and SMA3 (rs =-0.777, p = 0.028). Conclusions: This study reveals that nusinersen treatment in symptomatic pediatric SMA patients with motor improvement is linked to increased scoliosis progression in SMA1, whereas it is associated with decreased progression in SMA2 and SMA3. Age, baseline Cobb angle, and motor milestone improvement are influential factors in scoliosis progression.

Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study.

BACKGROUND AND OBJECTIVES: Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA. METHODS: In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points. RESULTS: Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported. DISCUSSION: Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA. TRIAL REGISTRATION INFORMATION: This trial is registered with ClinicalTrials.gov (NCT03921528). CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.

BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality. METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline. CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.

Longitudinal changes of swallowing safety and efficiency in infants with spinal muscular atrophy who received disease modifying therapies.

BACKGROUND: Dysphagia is a common feature of the natural history of patients with spinal muscular atrophy (SMA). Literature regarding swallowing safety and efficiency is scarce in patients with SMA, particularly in the era of newborn screening programs and disease-modifying therapies. OBJECTIVE: To describe the longitudinal changes of swallowing safety and efficiency in children with SMA who received one or more disease modifying therapies METHODS: Case series of patients with SMA followed at the University of Florida from 1 May 2019 to 31 December 2022 who had two or more videofluoroscopy swallowing studies (VFSS), with the first being within 30 days of their first treatment. Data extracted from the electronic health record included: neuromotor outcomes, VFSS penetration aspiration scores (PAS), presence of abrnormal oral or pharyngeal residue, clinical history, and timing of disease-modifying therapies administration. RESULTS: Seven subjects were included (five male); three were diagnosed via newborn screen. Median age at diagnosis was 10 days (range: 4-250). Median age at initial VFSS was 29 days (range: 9-246), and age at the last VFSS was 26.1 months (range: 18.2-36.2). All subjects received onasemnogene-abeparvovec (OA); four received additional therapies. PAS at diagnosis was abnormal in four subjects. Six subjects required feeding modifications after VFSS results. Of these, three had silent aspiration (PAS 8) and three of them improved after treatment. CONCLUSIONS: Swallowing safety and efficiency can be impaired in patients with SMA despite early treatment. Larger, prospective studies are needed to define optimal timiing of longitudinal instrumental evaluations.

Effect of nusinersen treatment on quality of life and motor function in adult patients with spinal muscular atrophy.

The aim of this study was to assess the effect of 4 loading doses of nusinersen on motor function and quality of life (QoL) in adult patients with spinal muscular atrophy (SMA). Twenty-one adult patients with genetically confirmed SMA who were treated with 4 loading doses of nusinersen were included in this study. All patients were evaluated with the Medical Research Council (MRC) scale, the Hammersmith Functional Motor Scale Expanded (HFMSE), and the Short Form Survey-36 (SF-36) at baseline (V1) and before the first nusinersen maintenance treatment, which was at the 15th month of treatment (V2). The SF-36 score was compared between the patients and 35 age-matched healthy controls. Of the twenty-one patients with a median age of 36 years, 10 were nonambulatory, and 11 were ambulatory. The physical component score and the mental component score of the SF-36 were significantly lower in the SMA patient group at baseline than in the healthy group. The median HFMSE scores significantly improved at V2 in both ambulatory and nonambulatory SMA patients (p < 0.05). The median MRC score significantly increased at V2 in the ambulatory SMA patient group (p = 0.04) but not in the nonambulatory SMA patient group (p = 0.19). There was a significant improvement in physical QoL in all the SMA patients at V2 (p = 0.02), but there was no significant improvement in mental QoL (p = 0.15). The loading nusinersen treatment significantly improved motor function scores, muscle strength, and physical QoL.

'Reading the palm' - A pilot study of grip and finger flexion strength as an outcome measure in 5q spinal muscular atrophy.

BACKGROUND: Innovative RNA modifying and gene replacement therapies are currently revolutionizing the therapeutic landscape in 5q-associated spinal muscular atrophy (SMA). In order to provide individual recommendations for choice of treatment and therapy (dis-) continuation, objective outcome measures are needed. The purpose of this study was to determine whether maximum isometric voluntary grip and finger flexion strength is a useful sensitive outcome measure in children and adult patients with SMA. METHODS: In this non-interventional, longitudinal pilot study, we assessed grip and finger flexion strength on 39 patients with SMA II and III (n = 16 children, mean age = 10.0; n = 23 adults, mean age = 38.4) using the Weber hand and finger dynamometer HFD 200. Grip and finger flexion strength, clinical examinations and motor function scores (Revised Upper Limb Module, Hammersmith Functional Motor Scale Expanded) were assessed over a 12-month treatment period concurrent with the nusinersen treatment. RESULTS: Grip and finger flexion strength was highly associated with motor function and disease severity, SMA type and SMN2 copy number. During nusinersen treatment, grip and finger flexion strength significantly increased in children and adults with SMA. CONCLUSION: Grip and finger flexion strength measured with the HFD 200 is a promising sensitive outcome measure for SMA.

Specificity, synergy, and mechanisms of splice-modifying drugs.

Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5' splice site sequences, suggest that branaplam recognizes 5' splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.

Risdiplam in Spinal Muscular Atrophy: Safety Profile and Use Through The Early Access to Medicine Scheme for the Paediatric Cohort in Great Britain.

Background: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021. Objective: To describe the largest paediatric European real-world set of data on patients' characteristics and short-term safety for risdiplam in Great Britain through EAMS. Methods: We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events. Results: Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0-17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients.Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified. Conclusions: This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam's role in addressing patients' needs into the future.

Real-World Outcomes in Patients with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec Monotherapy: Findings from the RESTORE Registry.

Background: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. Objective: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. Methods: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Results: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. Conclusion: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

Cost-Effectiveness of Onasemnogene Abeparvovec Compared With Nusinersen and Risdiplam in Patients With Spinal Muscular Atrophy Type 1 in Brazil: Custo-Efetividade do Onasemnogeno Abeparvoveque (AVXS-101) em Comparação ao Nusinersena e Risdiplam em Pacientes com Atrofia Muscular Espinhal Tipo 1 no Brasil.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of the onasemnogene abeparvovec in relation to nusinersen and risdiplam in the treatment of spinal muscular atrophy type 1 from the perspective of the Brazilian Unified Health System. METHODS: A Markov model was built on a lifetime horizon. Short-term data were obtained from clinical trials of the technologies and from published cohort survival curves (long term). Costs were measured in current 2022 local currency (R$) values and benefits in quality-adjusted life-years (QALYs). Utility values were derived from type 1 spinal muscular atrophy literature, whereas costs related to technologies and maintenance care in each health state were obtained from official sources of reimbursement in Brazil. Deterministic and probabilistic, as well as scenario, sensitivity analyses were performed. RESULTS: Compared with the less costly strategy (nusinersen), the use of onasemnogene abeparvovec resulted in an incremental cost of R$2.468.448,06 ($975 671.169 - purchasing power parity [PPP]) and a 3-QALY increment and incremental cost-effectiveness ratio of R$742.890,92 ($293 632.774 - PPP)/QALY. Risdiplam had an extended dominance from other strategies, resulting in an incremental cost-effectiveness ratio of R$926.586,22 ($366 239.612 - PPP)/QALY compared with nusinersen. Sensitivity analysis showed a significant impact of the follow-up time of the cohort and the cost of acquiring onasemnogene abeparvovec. CONCLUSIONS: Over a lifetime horizon, onasemnogene abeparvovec seems to be a potentially more effective option than nusinersen and risdiplam, albeit with an incremental cost. Such a trade-off should be weighed in efficiency criteria during decision making and outcome monitoring from the perspective of the Brazilian Unified Health System.

Spinal Muscular Atrophy Treatment: The MTOR Regulatory Intervention.

Spinal muscular atrophy (SMA) is a hereditary disorder affecting neurons and muscles, resulting in muscle weakness and atrophy. Most SMA cases are diagnosed during infancy or early childhood, the most common inherited cause of infant mortality without treatment. Still, SMA might appear at older ages with milder symptoms. SMA patients demonstrate progressive muscle waste, movement problems, tremors, dysphagia, bone and joint deformations, and breathing difficulties. The mammalian target of rapamycin (mTOR), the mechanistic target of rapamycin, is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases encoded by the mTOR gene in humans. The mTOR phosphorylation, deregulation, and autophagy have shown dissimilarity amongst SMA cell types. Therefore, exploring the underlying molecular process in SMA therapy could provide novel insights and pave the way for finding new treatment options. This paper provides new insight into the possible modulatory effect of mTOR/ autophagy in SMA management.

A case series evaluating patient perceptions after switching from nusinersen to risdiplam for spinal muscular atrophy.

INTRODUCTION/AIMS: In 2016, nusinersen became the first disease-modifying medication approved by the U.S. Food and Drug Administration (FDA) for spinal muscular atrophy (SMA). With the later availability of risdiplam in 2020, individuals now have the option of switching from nusinersen to risdiplam. Limited published data exist to inform this decision. This study aims to evaluate the perceptions and experiences of adult participants and parents of minor participants who previously received nusinersen and switched to risdiplam for the treatment of SMA. METHODS: Institutional Review Board (IRB) approval was obtained from the Wake Forest IRB prior to the initiation of this study. A cross-sectional, observational study, with qualitative and quantitative data gathered via questionnaire and medical record review, was performed. Inclusion criteria included (1) prior diagnosis of SMA, (2) previous treatment with nusinersen, and (3) change to treatment with risdiplam. No participants were excluded based on age. RESULTS: Fourteen participants-eight adults and six children-were enrolled in the study. Respondents noted improvements in physical function with each medication. Overall, respondents reported worse satisfaction with the method of delivery of the intrathecally delivered nusinersen compared to the orally-delivered risdiplam, but no respondent reported negative overall satisfaction with either medication. A majority (78.6%) of respondents reported that switching from nusinersen to risdiplam was the correct decision. DISCUSSION: These results suggest that most patients are satisfied when switching from nusinersen to risdiplam, with the method of delivery being a primary factor.

Monitoring Nusinersen Treatment Effects in Children with Spinal Muscular Atrophy with Quantitative Muscle MRI.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA. OBJECTIVE: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect. METHODS: We used a quantitative MRI protocol before start of treatment and following the 4th and 6th injection of nusinersen in 8 children with SMA type 2 and 3 during the first year of treatment. The MR protocol allowed DIXON, T2 mapping and diffusion tensor imaging acquisitions. We also assessed muscle strength and motor function scores. RESULTS: Fat fraction of all thigh muscles with the exception of the m. adductor longus increased in all patients during treatment (+3.2%, p = 0.02). WaterT2 showed no significant changes over time (-0.7 ms, p = 0.3). DTI parameters MD and AD demonstrate a significant decrease in the hamstrings towards values observed in healthy muscle. CONCLUSIONS: Thigh muscles of children with SMA treated with nusinersen showed ongoing fatty infiltration and possible normalization of thigh muscle microstructure during the first year of nusinersen treatment. Quantitative muscle MRI shows potential as biomarker for the effects of SMA treatment strategies.

Risdiplam Real World Data - Looking Beyond Motor Neurons and Motor Function Measures.

BACKGROUND: Risdiplam is an orally administered treatment for spinal muscular atrophy which leads to an improvement in motor function as measured by functional motor scales compared with placebo. Although risdiplam has been registered since 2020, real-world data in adults is still scarce. There have been no new safety signals so far, with some results pointing that risdiplam may be effectiveObjective:The objective was to present real-world data of 31 adult patients with spinal muscular atrophy type 2 and type 3 treated with risdiplam in the Republic of CroatiaMethods:Treatment effects were assessed with motor function tests and patient reported outcome measures, including Individualized Neuromuscular Quality of Life questionnaire, and Jaw Functional Limitation Scale. Side effects, as well as subjective improvements and symptoms, were noted. RESULTS: Majority of patients did not report any side effects. During treatment, we have observed clinically meaningful improvements in some patients, with stabilization of motor functions in the remaining patients. The majority of patients with bulbar function impairment experienced bulbar function improvement, all patients reported an increased quality of life with treatment. An unexpected observed treatment effect was weight gain in a third of all patients with some patients reporting an increase in appetite and subjective improvement in digestion. CONCLUSIONS: Risdiplam treatment was well tolerated with subjective and objective positive outcomes registered as measured by functional motor scales and patient-reported outcomes. Since risdiplam is administered orally and acts as a systemic therapy for a multisystemic disorder, effects in systems other than neuromuscular can be expected and should be monitored. Due to systemic nature of the disease patients need multidisciplinary monitoring.

A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models.

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.

Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to assess the efficacy and safety of risdiplam on motor and respiratory function in spinal muscular atrophy (SMA). We systematically searched Medline, Scopus, Web of Science, and the Cochrane Library from inception to March 2023. We included pre-post studies that determined the effect of risdiplam on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the 32-item Motor Function Measure (MFM32), the Revised Upper Limb Module (RULM), the Hammersmith Functional Motor Scale - Expanded (HFMSE), respiratory function, and the proportion of risdiplam-related adverse events in a population with SMA (phenotypes 1 and 2/3). Meta-analyses were also performed where possible. Eleven studies were included. After 12 months of treatment, 57% of participants with SMA1 achieved a CHOP-INTEND score ≥ 40 points, and more than half were able to feed orally and had head control. In SMA2/3, MFM32, RULM, and HFMSE increased by 2.09 (1.17, 3.01), 1.73 (1.25, 2.20), and 1.00 (0.40, 1.59) points, respectively. Efficacy on respiratory function in SMA2/3 was inconsistent. Finally, 16% of participants experienced adverse events, but serious adverse events could not be quantified due to a lack of cases. The limited available evidence suggests that risdiplam is an effective and safe drug for the treatment of SMA. In addition, long-term clinical benefit may be partly determined by the stage of disease at which treatment is initiated.

Later efficacy of nusinersen treatment in adult patients with spinal muscular atrophy: A retrospective case study with a median 4-year follow-up.

BACKGROUND: Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder characterized by skeletal muscle atrophy and weakness. New treatments for SMA have been developed namely, the drugs nusinersen, onasemnogene abeparvovec, and risdiplam. However, there are limited reports on their effects on adult patients with SMA, particularly over long periods. Therefore, this study aimed to determine the efficacy of nusinersen treatment in adult patients with SMA. METHODS: We retrospectively reviewed patients with SMA type 2 or 3 who received nusinersen treatment between January 2018 and January 2023. All patients were evaluated using the Hammersmith Functional Motor Scale-Expanded (HFMSE) before the commencement of nusinersen treatment, and the change with respect to the baseline HFMSE score was compared. RESULTS: A total of six patients, three patients each with SMA type 2 or 3, were treated with nusinersen. The median age of the patients before the commencement of nusinersen treatment was 51.5 years (range, 33-59 years), and the median treatment period was 50.5 months (range, 33-57 months). Three patients showed an increased tendency of improvement on the HFMSE at 15-26 months after nusinersen treatment, and the HFMSE score was maintained in two patients. Significant adverse events were observed in three patients: one subdural hematoma, one incidental bone fracture, and one cheek dermatofibrosarcoma. CONCLUSIONS: Nusinersen treatment showed later efficacy in adult patients with SMA type 2 or 3. The distinct efficacy of nusinersen requires further investigation using a large number of cases and a long follow-up period.