Search Results (36)

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by biallelic SMN1 gene loss, leading to motor neuron degeneration and progressive muscle weakness. The SMN protein is also implicated in telomerase biogenesis, suggesting a possible link between SMA and telomere regulation. This study aimed to investigate relative telomere length in pediatric SMA patients and evaluate, for the first time, the potential effects of gene replacement therapy with onasemnogene abeparvovec. Relative telomere length was measured in peripheral blood lymphocytes using quantitative real-time PCR in 58 patients and 58 age- and sex-matched healthy controls. Of the patients, 19 had received gene replacement therapy. SMA patients without this treatment exhibited significantly shorter telomeres compared with controls (p = 0.029), whereas no significant difference was observed between gene-treated patients and controls (p = 0.108). Direct comparison revealed longer telomeres in treated patients than in untreated ones (p = 0.012). These findings indicate that telomere attrition is present in SMA and may be mitigated by gene replacement. While the exact contribution of telomere biology to SMA pathogenesis remains to be clarified, telomere length may represent a biomarker for disease severity and treatment response, as well as a potential therapeutic target in this disorder. Full article

Background/Objectives: The approval of disease-modifying therapies has significantly improved outcomes for patients with spinal muscular atrophy (SMA), yet their long-term safety profiles remain under continuous evaluation. This study aimed to assess trends in the reporting of suspected adverse drug reactions (ADRs) associated with nusinersen, onasemnogene abeparvovec, and risdiplam across the European Union. Methods: We conducted a secondary analysis of annual suspected ADR data reported to EudraVigilance from 2017 to 2024 for the three approved disease-modifying therapies for SMA. On top of general reporting trend, specific adverse reactions of interest included post-lumbar puncture syndrome for nusinersen, liver toxicity and elevated serum troponin for onasemnogene abeparvovec, and respiratory and gastrointestinal reactions for risdiplam. Joinpoint regression analysis was used to evaluate annual percent changes and identify statistically significant trend segments for each medicine. Results: The reporting of suspected ADRs for nusinersen showed an initial increase, followed by a significant decline after 2019. Onasemnogene abeparvovec exhibited a continued but decelerating increase in suspected ADRs, while risdiplam demonstrated a consistent upward trend across all reported reactions. Conclusions: Diverging patterns in adverse reaction reporting suggest a stabilizing safety profile for nusinersen and potential emerging safety signals for risdiplam and onasemnogene abeparvovec, underscoring the need for ongoing continued pharmacovigilance (e.g., post-authorization studies and spontaneous reporting). Full article

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s first-year experience, focusing on screening yield, birth prevalence, clinical outcomes, and challenges. In the first year, 6 of 67,933 newborns screened positive for SMA, all subsequently confirmed by diagnostic testing. Of these, 4 newborns (67%) had two SMN2 copies and 2 newborns (33%) had four copies. Additionally, one symptomatic compound heterozygote infant presented during this period, indicating a provincial birth prevalence of 1 in 9705 live births (95% CI: 1:20,032–1:4701). Two newborns with two SMN2 copies were symptomatic at initial consultation; one transitioned to palliative care and died at 43 days of life. Surviving newborns initiated treatment at a median age of 30 days (range: 9–103 days), with four receiving onasemnogene abeparvovec and one nusinersen. Motor outcomes at three or six months were stable or improved among treated infants. Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program’s impact, which is expected with full automation. Full article

Background/Objectives: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease resulting in proximal muscle weakness and paralysis. SMA treatment has radically changed in the past 10 years thanks to the development of novel therapies such as nusinersen and onasemnogene abeparvovec. Since the advent of new treatments, the incidence and perioperative risk factors of patients with SMA undergoing longer, higher-risk surgeries are unknown. We hypothesized that patients with SMA would be at an overall elevated risk for postoperative pulmonary complications (PPC) and prolonged length of stay compared to the general population, but that this would be reduced in patients undergoing surgery in the years after the release of new therapies. Methods: Patients who underwent surgery at a continuously enrolled American College of Surgeons National Surgery Quality Improvement Program-Pediatric hospital from 1 January 2012, to 31 December 2021, were included in this study. Cases with missing covariate or primary outcome data were excluded from the analysis. Patients with ages greater than 17 years, preoperative tracheostomy, preoperative mechanical ventilation, missing covariate or primary outcome data were excluded. Patients with SMA were identified by their ICD-9 and 10 codes. A cutoff year of 2018 was chosen for analysis of the primary outcomes as this was a full year after nusinersen received FDA approval. Results: On univariable analysis, the risk for PPC in patients with SMA was reduced in patients undergoing surgery in 2018 or later compared to pre-2018 (pre-2018 OR 4.44, 95% CI 1.56–9.6, p = 0.008; post-2018 OR 3.48, 95% CI 0.84–9.12, p = 0.08). On multivariable analysis, the association between SMA and PPC substantially decreased in 2018 and after but was no longer statistically significant (pre-2018 OR 1.96, 95% CI 0.80–4.80, p = 0.14; post-2018 OR 1.03, 95% CI 0.33–3.26, p = 0.96). SMA was positively associated with LOS in the pre-2018 cohort, with a coefficient from a log linear model of 0.67 (95% CI 0.32–1.01; p < 0.001), and SMA adding an additional 1.93 days in LOS. For data post-2018, the effect of SMA on LOS was no longer statistically significant. Conclusions: Utilizing a large dataset, we found a reduced association between SMA and PPC a year following widespread implementation of SMN antisense oligonucleotide therapy, and a statistically significant reduction in LOS in patients with SMA after 2018. This may reflect improved motor outcomes and respiratory mechanics in the new treatment era. Full article

Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular disorder and a leading genetic cause of infant mortality. The past decade has witnessed a paradigm shift in SMA management with the advent of disease-modifying drugs (DMDs). This narrative review aims to (i) summarize pivotal randomized controlled trials (RCTs) that led to the approval of DMDs for SMA Types 1 and 2; (ii) synthesize real-world evidence on their safety and effectiveness; and (iii) explore emerging therapeutic frontiers, including gene modifiers, predictive biomarkers, prenatal interventions, and combination strategies. Pivotal RCTs and real-world studies demonstrate that onasemnogene abeparvovec (a single-dose gene therapy), nusinersen (an intrathecal antisense oligonucleotide), and risdiplam (an oral SMN2 splicing modifier) each significantly improve survival and motor function milestones compared to natural history in Type 1 and Type 2 SMA, with the majority of treated patients achieving independent sitting and prolonged ventilator-free survival, while safety profiles are generally manageable and distinct for each therapy. Similar outcomes have been demonstrated for presymptomatic patients with SMA. The introduction of DMDs has transformed the prognosis of SMA, particularly for early-onset forms, with robust evidence supporting their efficacy and safety. Continued real-world monitoring and exploration of adjunctive therapies are essential to optimize outcomes across the SMA setting and address unmet needs in non-responders and older patients. Full article

Background and aim: Advanced Therapy Medicinal Products (ATMPs) are innovative drugs based on genes, tissues, or cells that target rare and severe diseases. ATMPs have shown promising clinical outcomes but are associated with high costs, raising questions about cost-effectiveness. Hence, this systematic review aims to analyze the cost-effectiveness and cost-utility profiles of the European Medicines Agency-authorized ATMPs for treating rare diseases. Methods: A systematic review was conducted following PRISMA guidelines. Studies were identified by searching PubMed, Embase, Web of Science, and ProQuest scientific databases. Economic evaluations reporting incremental cost-effectiveness/utility ratios (ICERs/ICURs) for ATMPs were included. Costs were standardized to 2023 Euros, and a cost-effectiveness plane was constructed to evaluate the results against willingness-to-pay (WTP) thresholds of EUR 50,000, EUR 100,000, and EUR 150,000 per QALY, as part of a sensitivity analysis. Results: A total of 61 studies met the inclusion criteria. ATMPs for rare blood diseases, such as tisagenlecleucel and axicabtagene ciloleucel, were found to be cost-effective in a majority of studies, with incremental QALYs ranging from 1.5 to 10 per patient over lifetime horizon. Tisagenlecleucel demonstrated a positive cost-effectiveness profile in the treatment of acute lymphoblastic leukemia (58%), while axicabtagene ciloleucel showed a positive profile in the treatment of diffuse large B-cell lymphoma (85%). Onasemnogene abeparvovec for spinal muscular atrophy (SMA) showed uncertain cost-effectiveness results, and voretigene neparvovec for retinal diseases was not cost-effective in 40% of studies, with incremental QALYs around 1.3 and high costs exceeding the WTP threshold set. Conclusions: ATMPs in treating rare diseases show promising economic potential, but cost-effectiveness varies across indications. Policymakers must balance innovation with system sustainability, using refined models and the long-term impact on patient outcomes. Full article

Since its discovery in the late 19th century, spinal muscular atrophy (SMA) has had a significant medical and societal impact, primarily affecting newborns, toddlers, and young adults. While new pharmaceutical strategies are effective in treating SMA in a particular subset of patients, continued research is necessary to improve the well-being of patients. Treatments are needed for those who do not respond to newly approved drugs and older patients with significantly compromised neuron systems. After summarizing SMA genotypes, phenotypes, and approved pharmacological treatments, this review presents ongoing trials for approved and new molecules, new formulations, and administration methods. Based on the work of our lab, we also discuss nutritional interventions that aim to counteract the oxidative stress present in SMA cells. Finally, we assess rehabilitative interventions, focusing on psychological approaches. Full article

Background: Spinal muscular atrophy type 1 (SMA1) is a severe neuromuscular disorder characterized by progressive muscle weakness and atrophy, including the muscles of the oral cavity and esophagus. Eosinophilic esophagitis (EoE), a chronic, allergic disease, presents with eosinophilic infiltration of the esophagus, leading to esophageal dysmotility. Feeding difficulties may occur in both conditions. So far, the coexistence of EoE and SMA1 has not been described; we present the first such case. Case presentation: The patient was a girl with SMA1 diagnosed shortly after birth, treated with nusinersen and onasemnogene abeparvovec, and fed a standard industrial diet through a gastrostomy. In her second year of life, she developed increasing symptoms: distress during feeding, regurgitation, vomiting, and weight loss. She was treated with proton pump inhibitors without clinical improvement. Gastroscopy was performed, revealing superficial epithelial damage with bleeding in the proximal esophagus. Histopathology showed chronic inflammation with up to 150 eosinophils per high-power field, microabscesses, spongiosis, and basal layer hypertrophy. The girl was diagnosed with EoE. Her diet was switched from a standard industrial formula to an amino acid-based formula, which led to marked clinical improvement, the resolution of symptoms, and appropriate weight gain. Conclusions: This case report highlights the challenges of diagnosing EoE in SMA1 patients and emphasizes the need for multidisciplinary approaches and further investigation of allergic manifestations in SMA1 patients. Full article

Background/Objectives: Spinal muscular atrophy (SMA) treatment has evolved with the approval of nusinersen, onasemnogene abeparvovec, and risdiplam. This study aims to assess the post-marketing safety profile of these therapies through the spontaneous adverse drug reaction (ADR) reports available in EudraVigilance (EV). Methods: Data from EV were retrieved via adrreports.eu for the suspected ADRs associated with nusinersen, onasemnogene abeparvovec, and risdiplam from their approval in the European Economic Area (EEA) to 31 December 2024. The ADR reports were exported and analysed using descriptive statistics in Microsoft Excel. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated for suspected ADRs, focusing on reactions with a lower limit of the 95% CI exceeding 1. Results: A total of 3196, 806, and 956 individual case safety reports (ICSRs) were identified for nusinersen, onasemnogene abeparvovec, and risdiplam, respectively. The most frequently reported ADRs with significantly increased RORs included post-lumbar puncture syndrome (nusinersen: 11%), pyrexia (onasemnogene abeparvovec: 23%), and pneumonia (risdiplam: 9%). While some ADRs were therapy-specific, others were consistent with SMA disease progression and complications. Onasemnogene abeparvovec showed a notable prevalence of hepatotoxicity, while risdiplam was associated with gastrointestinal and respiratory events. Conclusions: To conclude, the analysis reinforces the known safety profiles of these SMA treatments while highlighting potential areas for further investigation. ADRs related to SMA complications require careful differentiation from true drug-related effects. Future pharmacovigilance efforts should focus on long-term safety assessments and real-world evidence to optimize treatment strategies. Full article

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease characterized by progressive muscle weakness and atrophy due to the absence of the survival motor neuron 1 (SMN1) gene. SMA is classified into types 0 through 4 based on the age of symptom onset and the severity of motor function decline. Recent advances in SMA treatment, including nusinersen, onasemnogene abeparvovec, and risdiplam, have significantly improved the prognosis of SMA patients. This study evaluated the safety and efficacy of nusinersen in pediatric patients with SMA types 1, 2, and 3 in a real-world clinical setting. Methods: This prospective observational single-center study assessed the treatment effects of nusinersen in 23 pediatric patients with genetically confirmed SMA over a 22-month observation period. All the participants received intrathecal loading doses of 12 mg of nusinersen on days 1, 14, 28, and 63, followed by maintenance doses every four months. Functional assessments were conducted using the CHOP-INTEND scale. Data were collected during routine patient visits, including clinical laboratory tests and vital sign parameters, and adverse events were recorded. The inclusion criteria were defined by the national reimbursement program for nusinersen treatment in Poland. Results: Initially, 37 patients ranging from 1 month old to 18 years old were included, but 23 were ultimately observed due to changes in treatment regimens or assessment scales. The patients showed significantly improved CHOP-INTEND scores over the 22-month period. At 6 months, the average increase was 4.2 points, continuing to 17.8 points at 22 months. By the end of the study, 100% of patients showed either stabilization or improvement, with significant clinical improvements observed in several patients. Nusinersen was generally well-tolerated, with post-lumbar puncture headache and lower back pain being the most common adverse events. Conclusions: Nusinersen treatment significantly enhances motor function in pediatric patients with SMA types 1, 2, and 3. This study demonstrates the importance of early and sustained treatment, with most patients showing the continuous improvement or stabilization of motor function. These findings support the use of nusinersen as an effective therapy for SMA; however, further research is needed to understand the long-term outcomes and optimize treatment strategies. Full article

Background: Spinal muscular atrophy (SMA) is a genetic disease characterized by loss of motor neurons in the spinal cord and lower brainstem. The term “SMA” usually refers to the most common form, 5q-SMA, which is caused by biallelic mutations in SMN1 (located on chromosome 5q13). However, long before the discovery of SMN1, it was known that other forms of SMA existed. Therefore, SMA is currently divided into two groups: 5q-SMA and non-5q-SMA. This is a simple and practical classification, and therapeutic drugs have only been developed for 5q-SMA (nusinersen, onasemnogene abeparvovec, risdiplam) and not for non-5q-SMA disease. Methods: We conducted a non-systematic critical review to identify the characteristics of each SMA disease. Results: Many of the non-5q-SMA diseases have similar symptoms, making DNA analysis of patients essential for accurate diagnosis. Currently, genetic analysis technology using next-generation sequencers is rapidly advancing, opening up the possibility of elucidating the pathology and treating non-5q-SMA. Conclusion: Based on accurate diagnosis and a deeper understanding of the pathology of each disease, treatments for non-5q-SMA diseases may be developed in the near future. Full article

Patients with spinal muscular atrophy type 1 (SMA-1) requiring invasive ventilation can be eligible for gene therapy if they tolerate at least 8 h off ventilation per day. We aimed to assess the short-term safety and efficacy of gene therapy (onasemnogene abeparvovec; Zolgensma) on respiratory function in SMA-1 patients ventilated via tracheostomy pre-gene therapy. A prospective cohort study included 22 patients. Patients were weaned off ventilation for at least 8 h daily by optimizing ventilator settings and duration, using cough augmentation, managing excessive airway secretions, enhancing nutrition, screening for respiratory bacterial colonization, and treating infections. Gene therapy was administered at a median age of 26 (Q1: 18, Q3: 43) months with a mean follow-up period of 7.64 (SD: 6.50) months. Gene therapy was safe and effective in resolving paradoxical breathing, improving cough ability, reducing airway secretions, and enhancing CHOP-INTEND scores. The clinical assessment and management implemented pre-gene therapy were effective in safely weaning patients for at least 8 h off ventilation daily. Gene therapy at a late age was safe and effective over the short-term period; however, long-term follow-up is recommended. In conjunction with gene therapy, high-quality clinical care is beneficial and should be paired with gene therapy. Full article

In the United States (U.S.), newborn screening (NBS) for spinal muscular atrophy (SMA) is implemented by individual states. There is likely variation in the practice patterns of state NBS programs and among the providers caring for newborns with SMA. This is a prospective, descriptive, observational study that seeks to quantify and describe practice patterns and heterogeneities in state NBS programs and provider practices in the U.S. We surveyed U.S. state NBS programs and care providers of newborns with SMA. Thirty states and 41 practitioners responded. NBS program practices vary by state. Most (74%) state programs provide results to both primary care and specialist providers and also defer confirmatory SMA testing to those providers. Two states had relatively high rates of false-positive or inclusive results. The total birth prevalence of SMA was 1:13,862. Most providers were in tertiary care centers (90%) and were child neurologists (81%) and/or had fellowship training in Neuromuscular Medicine or Electromyography (76%). All providers see new referrals in less than a week, but many do not initiate treatment until >3 weeks of age (39%), with most commonly reported delays related to insurance processes. Most (81%) prefer onasemnogene abeparvovec-xioi (OA) as the treatment of choice, mainly due to perceived efficacy and the route/frequency of administration. NBS practice patterns in the U.S. vary by state but overall yielded the predicted birth prevalence of positive results. Providers evaluate these newborns urgently, but many do not initiate therapy until after 3 weeks of age. Treatment delays are mainly related to insurance processes. Full article

Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic stage. This systematic review synthesises findings from prospective studies of presymptomatic treatment for 5q SMA published up to December 2023. The review identified three single-arm interventional studies of presymptomatic treatment (NURTURE, RAINBOWFISH, and SPR1NT), six observational studies comparing presymptomatic or screened cohorts versus symptomatic cohorts, and twelve follow-up studies of screened cohorts only (i.e., babies identified via newborn screening for SMA). Babies with three SMN2 copies met most motor milestones in the NURTURE study of nusinersen and in the SPR1NT study of onasemnogene abeparvovec. Babies with two SMN2 copies in these two studies met most motor milestones but with some delays, and some required ventilatory or feeding support. The RAINBOWFISH study of risdiplam is ongoing. Naïve comparisons of presymptomatic treatment in SPR1NT, versus untreated or symptomatic treatment cohorts, suggested improved outcomes in patients treated presymptomatically. Comparative observational studies supported the finding that presymptomatic treatment, and early treatment following screening, may improve outcomes compared with treatment at the symptomatic stage. Further research should assess the long-term clinical outcomes and cost-effectiveness of presymptomatic treatment for SMA. Full article