Treatment Of Spinal Muscular Atrophy Research Articles

Evaluation of inpatient and emergency department healthcare resource utilization and costs pre- and post-nusinersen for the treatment of spinal muscular atrophy using United States claims.

Aim: Nusinersen, administered by intrathecal injection at a dose of 12mg, is indicated across all ages for the treatment of spinal muscular atrophy (SMA). Evidence on real-world healthcare resource use (HRU) and costs among patients taking nusinersen remains limited. This study aimed to evaluate real-world HRU and costs associated with nusinersen use through US claims databases. Patients & methods: Using the Merative™ MarketScan® Research Databases, patients with SMA receiving nusinersen were identified from commercial (January 2017 to June 2020) and Medicaid claims (January 2017 to December 2019). Those likely to have complete information on the date of nusinersen initiation and continuous enrollment 12months pre- and post-index (first record of nusinersen treatment) were retained. Number and costs (US$ 2020) of inpatient admissions and emergency department (ED) visits, unrelated to nusinersen administration, were evaluated for 12months pre- and post-nusinersen initiation and stratified by age: pediatric (<18years) and adult (≥18years). Results: Overall, 103 individuals treated with nusinersen were retained: 59 were pediatric (mean age [range]: 9 [1-17] years), and 44 were adults (30 [18-63] years). Inpatient admissions decreased by 41% for pediatrics and 67% for adults in the 12months post-treatment versus the 12months pre-treatment. Average inpatient admission costs per patient for the pediatric cohort decreased by 63% ($22,903 vs $8466) and by 79% ($13,997 vs $2899) for the adult cohort when comparing the 12months pre-index with the 12months post-index period. Total ED visits and ED visit costs decreased by 8% and 35%, respectively, for the overall cohort over the 12-month period pre- and post-index. Conclusion: Using US claims databases, nusinersen treatment in pediatric and adult patients was associated with reductions in HRU and costs over a 12-month period post-treatment initiation relative to the pre-treatment period.

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.

Nusinersen Treatment for Spinal Muscular Atrophy: Retrospective Multicenter Study of Pediatric and Adult Patients in Kuwait.

Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is to describe the efficacy and safety of nusinersen in treating spinal muscular atrophy in 20 pediatric and 18 adult patients across six treatment centers in Kuwait. Functional motor assessments (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module) were used to assess changes in motor function following nusinersen treatment. The safety assessment involved clinical monitoring of adverse events. The results demonstrate clinically meaningful or considerable improvement in motor performance for nearly all patients, lasting over 4 years in some cases. A total of 70% of patients in the pediatric cohort and 72% of patients in the adult cohort achieved a clinically meaningful improvement in motor function following nusinersen treatment. Additionally, nusinersen was well-tolerated in both cohorts. These findings add to the growing body of evidence relating to the clinical efficacy and safety of nusinersen.

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.

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

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions and/or mutations in the survival of motor neuron1 (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. This retrospective study examined real-worldadherence and persistence with risdiplamfrom 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 ≥ 90days. Patients were included if the time between the index date and study observation period was ≥ 12months, 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. The proportion of patients (N = 1636) adherent at 12months 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 330.4days. The highest proportion of patients who were persistent were on Medicaid (81%). These findings demonstrate that patient adherence to and persistence with risdiplam treatment were high, including across all subgroups tested.

A consensus survey of neurologists and clinical geneticists on spinal muscular atrophy treatment in Singapore

Just a decade ago, spinal muscular atrophy (SMA) was considered a debilitating, progressive neuromuscular disease that inevitably led to chronic disability and a shortened lifespan. Now, it is treatable with nusinersen, onasemnogene abeparvovec (OAV) and risdiplam—the 3 disease-modifying drugs approved by the US Food and Drug Administration, the European Medicines Agency and most recently, the Health Science Authority in Singapore.1 Clinical trials and real-world data have consistently shown improvement in motor milestones for all 3 drugs, especially if introduced early in the disease course.2-4 More significantly, presymptomatic treatment has enabled age-appropriate development of motor milestones, leading to improved respiratory, orthopaedic and nutritional outcomes.

Diving into progress: a review on current therapeutic advancements in spinal muscular atrophy

Spinal muscular atrophy (SMA) is an uncommon disorder associated with genes characterized by the gradual weakening and deterioration of muscles, often leading to substantial disability and premature mortality. Over the past decade, remarkable strides have been made in the field of SMA therapeutics, revolutionizing the landscape of patient care. One pivotal advancement is the development of gene-targeted therapies, such as nusinersen, onasemnogene abeparvovec and risdiplam which have demonstrated unprecedented efficacy in slowing disease progression. These therapies aim to address the root cause of SMA by targeting the survival motor neuron (SMN) gene, effectively restoring deficient SMN protein levels. The advent of these innovative approaches has transformed the prognosis for many SMA patients, offering a glimmer of hope where there was once limited therapeutic recourse. Furthermore, the emergence of small molecule compounds and RNA-targeting strategies has expanded the therapeutic arsenal against SMA. These novel interventions exhibit diverse mechanisms of action, including SMN protein stabilization and modulation of RNA splicing, showcasing the multifaceted nature of SMA treatment research. Collective efforts of pharmaceutical industries, research centers, and patient advocacy groups have played an important role in expediting the translation of scientific discoveries into visible clinical benefits. This review not only highlights the remarkable progress achieved in SMA therapeutics but also generates the ray of hope for the ongoing efforts required to enhance accessibility, optimize treatment strategies, rehabilitation (care and therapies) and ultimately pave the way for an improved quality of life for individuals affected by SMA.

Male Reproduction in Spinal Muscular Atrophy (SMA) and the Potential Impact of Oral Survival of Motor Neuron 2 (SMN2) Pre-mRNA Splicing Modifiers.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene resulting in reduced levels of SMN protein. SMN protein is produced by cells throughout the body, and evidence suggests that low SMN protein can have systemic implications, including in male reproductive organs. However, a paucity of research exists on this important topic. This article will discuss findings from non-clinical studies on the role of SMN in the male reproductive system; additionally, real-world observational reports of individuals with SMA will be examined. Furthermore, we will review the non-clinical reproductive findings of risdiplam, a small-molecule SMN2 splicing modifier approved for the treatment of SMA, which has widespread distribution in both the central nervous system and peripheral organs. Specifically, the available non-clinical evidence of the effect of risdiplam on male reproductive organs and spermatogenesis is examined. Lastly, the article will highlight available capabilities to assess male fertility as well as the advanced reproductive technologies utilized to treat male infertility. This article demonstrates the need for further research to better understand the impacts of SMA on male fertility and reproduction.

JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam.

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017.

Long-Term Comparative Efficacy and Safety of Risdiplam and Nusinersen in Children with Type1 Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type1 SMA never sit independently and require increasing levels of ventilatory support as the disease progresses. Without intervention, and lacking ventilatory support, death typically occurs before the age of 2years. There are currently no head-to-head trials comparing available treatments in SMA. Indirect treatment comparisons are therefore needed to provide information on the relative efficacy and safety of SMA treatments for healthcare decision-making. The long-term efficacy and safety of risdiplam versus nusinersen in children with type1 SMA was evaluated using indirect treatment comparison methodology to adjust for differences between population baseline characteristics, to reduce any potential bias in the comparative analysis. An unanchored matching-adjusted indirect comparison was conducted using risdiplam data from 58 children in FIREFISH (NCT02913482) and published aggregate nusinersen data from 81 children obtained from the ENDEAR (NCT02193074) and SHINE (NCT02594124) clinical trials with at least 36months of follow-up. Children with type1 SMA treated with risdiplam had a 78% reduction in the rate of death, an 81% reduction in the rate of death or permanent ventilation, and a 57% reduction in the rate of serious adverse events compared with children treated with nusinersen. Children treated with risdiplam also had a 45% higher rate of achieving a Hammersmith Infant Neurological Examination, Module2 motor milestone response and a 186% higher rate of achieving a ≥ 4-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders compared with children treated with nusinersen. Long-term data supported risdiplam as a superior alternative to nusinersen in children with type1 SMA. Video abstract available for this article. Video abstract (MP4 184542 KB).

Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant.

Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild-type SMN (SMNWT). A severe SMA mouse model, SMA type 1.5 (Smn-/-; SMN2+/+; SMN∆7+/-) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMNWT and AAV9-SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle. AAV9-SMNK186R-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMNWT-treated mice. Lifespan increased by more than 10-fold in AAV9-SMNK186R-treated mice (144.8±26.11days) as compared with AAV9-SMNWT-treated mice (26.8±1.41days). AAV9-SMNK186R-treated mice showed an ascending weight pattern, unlike AAV9-SMNWT-treated mice, which only gained weight until P20 up to 5g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9-SMNK186R-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMNWT-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMNK186R-treated mice, unlike AAV9-SMNWT-treated mice that showed clasping phenotype for more than 20 out of 30s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMNK186R-treated mice compared with AAV9-SMNWT-treated mice without prominent neurotoxicity. AAV9-SMNK186R had fewer liver defects compared with AAV9-SMNWT, as judged by increased proliferation of hepatocytes (P<0.0001) and insulin-like growth factor-1 production (P<0.0001). Especially, low-dose AAV9-SMNK186R (nine-fold) also reduced clasping time compared with SMNWT. SMNK186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMNK186R can reduce the adverse events of Zolgensma. Collectively, SMNK186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.

Early spinal muscular atrophy treatment following newborn screening: A 20-month review of the first Italian regional experience.

Mandatory newborn screening (NBS) for spinal muscular atrophy (SMA) was implemented for the first time in Italy at the end of 2021, allowing the identification and treatment of patients at an asymptomatic stage. DNA samples extracted from dried blood spot (DBS) from newborns in Apulia region were analysed for SMA screening by using a real-time PCR-based assay. Infants harbouring homozygous deletion of SMN1 exon 7 confirmed by diagnostic molecular tests underwent clinical and neurophysiological assessment and received a timely treatment. Over the first 20 months since regional NBS introduction, four out of 42,492 (0.009%) screened children were found to carry a homozygous deletion in the exon 7 of SMN1 gene, with an annual incidence of 1:10,623. No false negatives were present. Median age at diagnosis was 7 days and median age at treatment was 20.5 days. Three of them had two copies of SMN2 and received gene therapy, while the one with three SMN2 copies was treated with nusinersen. All but one were asymptomatic at birth, showed no clinical signs of disease after a maximum follow-up of 16 months and reached motor milestones appropriate with their age. The minimum interval between diagnosis and the treatment initiation was 9 days. The timely administration of disease-modifying therapies prevented presymptomatic subjects to develop disease symptoms. Mandatory NBS for SMA should be implemented on a national scale.

Lifesaving Treatments for Spinal Muscular Atrophy: Global Access and Availability (P5-4.003)

Lifesaving Treatments for Spinal Muscular Atrophy: Global Access and Availability (P5-4.003)

Spinal Muscular Atrophy Treatment: The MTOR Regulatory Intervention.

mTOR: mammalian/mechanistic target of rapamycin; SMA: spinal muscular atrophy; IGF-1R: insulin-like growth factor type 1 receptor; FOXO3A: Forkhead box class O 3A; eIF4EBP1: eukaryotic translation initiation factor 4E-binding protein 1; Atrogin-1 (FBOX32): atrophy gene-1 (F-box only protein 32); TRAF2: TNF receptor-associated factor 2; p38 (MAPK14): p38 (mitogen-activated protein kinase 14); RRAS2: RAS related 2; ERK (MAPK1): extracellular signal-regulated kinase 1/2 (mitogen-activated protein kinase 1); SBMA: spinal and bulbar muscular atrophy; SMN: survival motor neuron; Akt: protein kinase B; MAFbx/atrogin-1: muscle atrophy F-box; MuRF-1: muscle RING-finger protein-1; WT: wild-type; GC-KLF15-BCAA: circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid; SBMA: spinal and bulbar muscular atrophy; PGC1α: proliferator-activated receptor γ coactivator 1 alpha CTRP3: C1q/TNF-related protein 3; SMN: survival motor neuron; VEGF: vascular endothelial growth factor; PTEN: phosphatase and tensin homolog.

Real-world evidence: Risdiplam in a patient with spinal muscular atrophy type I with a novel splicing mutation and one SMN2 copy.

Spinal muscular atrophy (SMA), which results from the deletion or/and mutation in the SMN1 gene, is an autosomal recessive neuromuscular disorder that leads to weakness and muscle atrophy. SMN2 is a paralogous gene of SMN1. SMN2 copy number affects the severity of SMA, but its role in patients treated with disease modifying therapies is unclear. The most appropriate individualized treatment for SMA has not yet been determined. Here, we reported a case of SMA type I with normal breathing and swallowing function. We genetically confirmed that this patient had a compound heterozygous variant: one deleted SMN1 allele and a novel splice mutation c.628-3T>G in the retained allele, with one SMN2 copy. Patient-derived sequencing of 4 SMN1 cDNA clones showed that this intronic single transversion mutation results in an alternative exon (e)5 3' splice site, which leads to an additional 2 nucleotides (AG) at the 5' end of e5, thereby explaining why the patient with only one copy of SMN2 had a mild clinical phenotype. Additionally, a minigene assay of wild type and mutant SMN1 in HEK293T cells also demonstrated that this transversion mutation induced e5 skipping. Considering treatment cost and goals of avoiding pain caused by injections and starting treatment as early as possible, risdiplam was prescribed for this patient. However, the patient showed remarkable clinical improvements after treatment with risdiplam for 7months despite carrying only one copy of SMN2. This study is the first report on the treatment of risdiplam in a patient with one SMN2 copy in a real-world setting. These findings expand the mutation spectrum of SMA and provide accurate genetic counseling information, as well as clarify the molecular mechanism of careful genotype-phenotype correlation of the patient.

Assessment of Barriers to Referral and Appointment Wait Times for the Evaluation of Spinal Muscular Atrophy (SMA): Findings from a Web-Based Physician Survey.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Clinical trial data suggest early diagnosis and treatment are critical. The purpose of this study was to evaluate neurology appointment wait times for newborn screening identified infants, pediatric cases mirroring SMA symptomatology, and cases in which SMA is suspected by the referring physician. Approaches for triaging and expediting referrals in the US were also explored. Cure SMA surveyed healthcare professionals from two cohorts: (1) providers affiliated with SMA care centers and (2) other neurologists, pediatric neurologists, and neuromuscular specialists. Surveys were distributed directly and via Medscape Education, respectively, between July 9, 2020, and August 31, 2020. Three hundred five total responses were obtained (9% from SMA care centers and 91% from the general recruitment sample). Diagnostic journeys were shorter for infants eventually diagnosed with SMA Type 1 if they were referred to SMA care centers versus general sample practices. Appointment wait times for infants exhibiting "hypotonia and motor delays" were significantly shorter at SMA care centers compared to general recruitment practices (p = 0.004). Furthermore, infants with SMA identified through newborn screening were also more likely to be seen sooner if referred to a SMA care center versus a general recruitment site. Lastly, the majority of both cohorts triaged incoming referrals. The average wait time for infants presenting at SMA care centers with "hypotonia and motor delay" was significantly shorter when initial referrals were triaged using a set of "key emergency words" (p = 0.036). Infants directly referred to a SMA care center versus a general sample practice were more likely to experience shorter SMA diagnostic journeys and appointment wait times. Triage guidelines for referrals specific to "hypotonia and motor delay" including use of "key emergency words" may shorten wait times and support early diagnosis and treatment of SMA.

Switching from Nusinersen to Risdiplam: A Croatian Real-World Experience on Effectiveness and Safety.

(1) Background: Data on combination or sequential treatment of spinal muscular atrophy (SMA) with disease-modifying drugs (DMDs) are missing and the latter field is poorly understood. The currently available data of patients on risdiplam previously treated with nusinersen are coming from exploratory research mainly focused on safety. Our aim was to investigate the real-world effectiveness (hypothesising non-inferiority) and safety profile of risdiplam in a paediatric-and-adult nusinersen-risdiplam spinal muscular atrophy switch cohort. (2) Methods: A retrospective and anonymous collection of relevant demographic and clinical data for all Croatian SMA patients switched from nusinersen to risdiplam up to September 2023 (reimbursed by Croatian Health Insurance Fund-CHIF) was performed using the CHIF database and associated reimbursement documentation. Patients were included in effectiveness and safety analysis if they met the following inclusion criteria: (i) risdiplam was reimbursed by the CHIF; (ii) the patient received at least six doses of nusinersen before the switch to risdiplam; (iii) there was no relevant pause between the latter disease-modifying drugs; (iv) availability of all prespecified studied data and parameters. (3) Results: In total, 17 patients met the inclusion criteria (58.9% female; median age 12.75 (3.0-44.5) years). In our 'switch' cohort, we demonstrated a non-inferiority of risdiplam to nusinersen in the SMA 1 (+1.0 in CHOP INTEND; p = 0.067), SMA 3p (+0.7 in HFMSE; p = 0.897), and SMA 3a (+0.8 in RHS; p = 0.463) subpopulations, during a one-year follow-up period. There were no reports on respiratory function worsening, feeding worsening, and no lethal events. No new safety concerns were identified, except for the weight gain that arose as a new potential adverse drug reaction 'signal' in two patients. (4) Conclusions: We have reported pivotal real-world findings on switching SMA patients from nusinersen to risdiplam and demonstrated its effectiveness (non-inferiority), safety, and tolerability in a heterogenous paediatric-and-adult 'switch' cohort; this will further increase the quality and standards of care as well as safety of a notable portion of SMA patients, especially for those who demand the switch from nusinersen to other DMDs for clinical or personal reasons.

Depletion of SMN protein in mesenchymal progenitors impairs the development of bone and neuromuscular junction in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in peripheral tissues plays a key role in the pathogenesis of SMA. Using limb mesenchymal progenitor cell (MPC)-specific SMN-depleted mouse models, we reveal that SMN reduction in limb MPCs causes defects in the development of bone and neuromuscular junction (NMJ). Specifically, these mice exhibited impaired growth plate homeostasis and reduced insulin-like growth factor (IGF) signaling from chondrocytes, rather than from the liver. Furthermore, the reduction of SMN in fibro-adipogenic progenitors (FAPs) resulted in abnormal NMJ maturation, altered release of neurotransmitters, and NMJ morphological defects. Transplantation of healthy FAPs rescued the morphological deterioration. Our findings highlight the significance of mesenchymal SMN in neuromusculoskeletal pathogenesis of SMA and provide insights into potential therapeutic strategies targeting mesenchymal cells for the treatment of SMA.

Depletion of SMN protein in mesenchymal progenitors impairs the development of bone and neuromuscular junction in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in peripheral tissues plays a key role in the pathogenesis of SMA. Using limb mesenchymal progenitor cell (MPC)-specific SMN-depleted mouse models, we reveal that SMN reduction in limb MPCs causes defects in the development of bone and neuromuscular junction (NMJ). Specifically, these mice exhibited impaired growth plate homeostasis and reduced insulin-like growth factor (IGF) signaling from chondrocytes, rather than from the liver. Furthermore, the reduction of SMN in fibro-adipogenic progenitors (FAPs) resulted in abnormal NMJ maturation, altered release of neurotransmitters, and NMJ morphological defects. Transplantation of healthy FAPs rescued the morphological deterioration. Our findings highlight the significance of mesenchymal SMN in neuromusculoskeletal pathogenesis of SMA and provide insights into potential therapeutic strategies targeting mesenchymal cells for the treatment of SMA.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.