Myasthenia gravis with tongue muscle atrophy: A case series.

Here, we presented 6 patients who were admitted to our institution and diagnosed as myasthenia gravis (MG) with tongue muscle atrophy. All these 6 patients developed symptoms of bulbar muscle weakness in acetylcholine receptor antibodies positive MG (AChR-MG) (3/6), muscle-specific receptor tyrosine kinase antibodies positive MG (MuSK-MG) (1/6), and sero-negative MG (2/6). Most of patients had "triple-furrowed" tongue except for patient 2 with irregular atrophy of tongue muscle. Tongue muscle atrophy occurs in patients with MuSK-MG, AChR-MG, and sero-negative MG. Atrophied tongue muscles of five patients with MG were reversible after immunotherapy.

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

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

Multidisciplinary approach on divergent outcomes in spinal muscular atrophies: comparing DYNC1H1 and SMN1 gene mutations.

Spinal Muscular Atrophy (SMA) emerges as a prominent genetic neuromuscular disorder primarily caused by variants in the survival motor neuron (SMN) gene. However, it is noteworthy that alternative variants impacting DYNC1H1 have also been linked to a subtype known as spinal muscular atrophy lower extremity predominant (SMA-LED). This observation underscores the complexity of SMA and highlights the necessity for tailored, gene-specific management strategies. Our study elucidates how similar approaches to managing SMA can yield distinct outcomes, emphasizing the imperative for personalized gene-based interventions in effectively addressing these conditions. Two patients were referred for further management due to clinical suspicion of type-3 SMA. The definitive diagnosis was confirmed through the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique, as well as whole-exome sequencing (WES). The analysis revealed deletions in exon-7 and 8 of SMN1 in the first patient and a likely pathogenic mutation (NM_001376.5(DYNC1H1):c.1867 T > C (NP_001367.2: p.Phe623Leu)) in DYNC1H1 in the second patient. Both patients presented with lower limb muscle weakness. However, while the first patient exhibited a gradual increase in severity over the years, the second patient displayed no progressive symptoms. The management was adjusted accordingly based on the genetic findings. Our observation underscores the complexity of SMA and highlights the necessity for tailored, gene-specific management strategies. Our study elucidates how similar approaches to managing SMA can yield distinct outcomes, emphasizing the imperative for personalized gene-based interventions in effectively addressing these conditions.

Subclinical spinal muscular atrophy in a 60-year-old man.

Spinal muscular atrophy is an autosomal recessive genetic disease that can manifest with different phenotypes, classified as types 1 to 4, being type 4 the mildest form. We report a case of a 60-year-old man presenting with sudden onset of numbness in the right upper limb and with a family history of a 48-year-old brother with progressive weakness. At the first visit, his exam was unremarkable, except for a mild paresis of the right elbow extension and reduced right bicipital and tricipital reflexes. Electromyography revealed chronic motor neuronopathy and the genetic study confirmed a diagnosis of spinal muscular atrophy. At the follow-up visit his complains improved and his neurologic exam returned to normal. To our knowledge, this patient is the oldest asymptomatic SMA individual ever reported. This case highlights the need to exclude late onset spinal muscular atrophy in patients with indolent motor neuronopathy.

Low phase angle: A predictor of functional status and discharge disposition in acute stroke older patients.

BACKGROUND & AIMS: This study aimed to investigate the effects of low phase angle (PhA) on functional status and discharge disposition during the acute phase in older patients with acute stroke. METHODS: We included consecutive patients who experienced acute stroke between October 2021 and December 2022. The exclusion criteria included: age<65 years, admission from other than home, death during hospitalization, inability to measure bioelectrical impedance analysis owing to implantation, and missing data. We defined low PhA (<5.28° for male and <4.62° for female) and categorized them into the low PhA group and normal group. The clinical outcomes were functional independence by the modified Rankin Scale (mRS) score (0-2, independence; 3-5, nonindependence) and discharge disposition (home or others). We used multivariate logistic regression analysis to examine the effect of low PhA on the mRS score at discharge and discharge disposition. RESULTS: Ultimately, a total of 205 patients were included in this analysis. More patients in the low PhA group were unable to be independent (27.7% vs. 66.7%, P < 0.001) and were unable to be discharged home (53.4% vs. 82.5%, P < 0.001) than in the normal group. Logistic regression analysis of the mRS scores showed that baseline low PhA decreased the likelihood of functional independence (odds ratio [OR] = 0.275, P = 0.003) and home discharge (OR = 0.378, P = 0.044). CONCLUSIONS: Low PhA is a risk factor for low functional status at hospital discharge; it decreases the likelihood of home discharge in older patients with acute stroke.

Epidemiology of Spinal Muscular Atrophy Based on the Results of a Large-Scale Pilot Project on 202,908 Newborns.

BACKGROUND: This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies. METHODS: The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA. RESULTS: In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors. CONCLUSIONS: The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements.

Polysomnography findings and respiratory muscle function in infants with early onset spinal muscular atrophy after gene replacement as monotherapy: A prospective study.

BACKGROUND: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy. METHODS: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly. RESULTS: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH2O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation. CONCLUSION: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters.

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.

Beyond Contractures in Spinal Muscular Atrophy: Identifying Lower-Limb Joint Hypermobility.

Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = -0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = -0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies.

Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Systemic LPS Administration Stimulates the Activation of Non-Neuronal Cells in an Experimental Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells' reactive phenotype.

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 24 months 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.

Transcriptome- and proteome-wide effects of a circular RNA encompassing four early exons of the spinal muscular atrophy genes.

Spinal muscular atrophy (SMA) genes, SMN1 and SMN2 (hereinafter referred to as SMN1/2), produce multiple circular RNAs (circRNAs), including C2A-2B-3-4 that encompasses early exons 2A, 2B, 3 and 4. C2A-2B-3-4 is a universally and abundantly expressed circRNA of SMN1/2. Here we report the transcriptome- and proteome-wide effects of overexpression of C2A-2B-3-4 in inducible HEK293 cells. Our RNA-Seq analysis revealed altered expression of ~ 15% genes (4172 genes) by C2A-2B-3-4. About half of the affected genes by C2A-2B-3-4 remained unaffected by L2A-2B-3-4, a linear transcript encompassing exons 2A, 2B, 3 and 4 of SMN1/2. These findings underscore the unique role of the structural context of C2A-2B-3-4 in gene regulation. A surprisingly high number of upregulated genes by C2A-2B-3-4 were located on chromosomes 4 and 7, whereas many of the downregulated genes were located on chromosomes 10 and X. Supporting a cross-regulation of SMN1/2 transcripts, C2A-2B-3-4 and L2A-2B-3-4 upregulated and downregulated SMN1/2 mRNAs, respectively. Proteome analysis revealed 61 upregulated and 57 downregulated proteins by C2A-2B-3-4 with very limited overlap with those affected by L2A-2B-3-4. Independent validations confirmed the effect of C2A-2B-3-4 on expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation and neuromuscular junction formation. Our findings reveal a broad role of C2A-2B-3-4, and expands our understanding of functions of SMN1/2 genes.

Assessing the Swallowing Function in Children with Spinal Muscular Atrophy: An Easily Accessible and Objective Multidimensional Approach.

Background: Spinal muscular atrophy (SMA), a genetic neuromuscular disease caused by lack of survival of motor neuron (SMN) protein, is characterized by muscular atrophy and respiratory and bulbar dysfunction. While swallowing disorders are common, they remain poorly studied. Objectives: Our study aimed to explore 1) intraoral pressure measurements with the Iowa Oral Performance Instrument system and the reliability of a Swallowing Function Assessment Questionnaire (SFAQ) in healthy controls, and 2) evaluate their use as swallowing function biomarkers and the evolution of swallowing function over time in children with SMA. Methods: We recruited 53 healthy children and 27 SMA patients all treated with SMN gene modulator therapy. Participants completed the SFAQ and underwent at least one measurement of maximal oral pressures (lingual, labial, and masseter). Results: Mean oral normalized pressure index were lower (all sites p < 0.001) and mean SFAQ scores were higher (p < 0.001) in patients compared with healthy controls. Pressure evolution over 1 year in SMA patients for all three oral sites did not show significant differences. SFAQ scores correlated negatively with oral pressures at all three sites in patients. Conclusions: Both tools provided new insights on the oral and pharyngeal phase of swallowing in SMA patients. In SMA patients, muscle strength in certain crucial anatomical regions during swallowing is weaker than in healthy children.

Chronic Pain in Patients with Spinal Muscular Atrophy in Switzerland: A Query to the Spinal Muscular Atrophy Registry.

Background and Objectives: Chronic pain is a common symptom in various types of neuromuscular disorders. However, for patients with spinal muscular atrophy (SMA), the literature regarding chronic pain is scarce. Thus, this study assessed the prevalence of chronic pain in children, adolescents, and adults with SMA and investigated the influence of clinical characteristics on chronic pain. Materials and Methods: This study used data from 141 patients, which were collected by the Swiss Registry for Neuromuscular Disorders. Extracted data included information on pain (present yes/no, pain location, and pain medication) and clinical characteristics, such as SMA type, motor function, wheelchair use, scoliosis, and contractures. Results: The analyses revealed that the highest prevalence of chronic pain was observed in adolescents with 62%, followed by adults with 48%, children (6-12 years) with 39%, and children < 6 years with 10%. The legs, back, and hips were most frequently reported as pain locations. Sex (females), age (adolescents), and the presence of contractures and scoliosis (with surgery) were factors that were associated with chronic pain. Conclusions: These findings contribute to a better understanding of pain in SMA, shedding light on its prevalence and characteristics in different age groups, which underscores the importance of assessing and managing pain in patients with SMA.

Relationship Between Hand Strength and Function in Duchenne Muscular Dystrophy and Spinal Muscular Atrophy: Implications for Clinical Trials.

BACKGROUND: Measurement of muscle strength and motor function is recommended in clinical trials of neuromuscular diseases, but the loss of hand strength at which motor function is impacted is not documented. OBJECTIVES: To establish the relationship between hand strength and function, and to determine the strength threshold that differentiates normal and abnormal hand function in individuals with Duchenne Muscular Dystrophy (DMD) or Spinal Muscular Atrophy (SMA). METHODS: Maximal handgrip and key pinch strength were measured with the MyoGrip and MyoPinch dynamometers, respectively. Hand function was assessed using the MoviPlate, the Motor Function Measure items for distal upper limb (MFM-D3-UL) and the Cochin Hand Function Scale (CHFS). Results: Data from 168 participants (91 DMD and 77 SMA, age 6-31 years) were analyzed. Relationships between strength and function were significant (P < 0.001). Hand function was generally preserved when strength was above the strength threshold determined by Receiver-Operating Characteristic (ROC) analysis: For MFM-D3-UL, the calculated handgrip strength thresholds were 41 and 13% of the predicted strength for a healthy subject (% pred) and the key pinch strength thresholds were 42 and 26% pred for DMD and SMA, respectively. For the MoviPlate, handgrip strength thresholds were 11 and 8% pred and key pinch strength thresholds were 21 and 11% pred for DMD and SMA, respectively. For participants with sub-threshold strength, hand function scores decreased with decreasing strength. At equal % pred strength, individuals with SMA had better functional scores than those with DMD. CONCLUSIONS: Hand function is strength-dependent for most motor tasks. It declines only when strength falls below a disease-specific threshold. Therefore, therapies capable of maintaining strength above this threshold should preserve hand function.

Onasemnogene Abeparvovec Administration via Peripherally Inserted Central Catheter: A Case Report.

Onasemnogene abeparvovec (OA) is the approved intravenous gene therapy for the treatment of spinal muscular atrophy (SMA). A functional copy of the human SMN1 gene was inserted into the target motor neuron cells via a viral vector, AAV9. In clinical trials, OA was infused through a peripheral venous catheter, and no data are available on central catheter use. Recently, we had a case where OA was administered directly into the right atrium via a peripherally inserted central catheter (PICC) instead of a peripheral line, as recommended. The patient was a female child aged 4 months, diagnosed as SMA type I. For practical reasons, a dose of OA according to the weight of the patient (1.1 × 1014 vectorial genomes/kg) was administered via PICC in 1 h, as the product information recommends. The drug was well tolerated, with no hypersensitivity reactions or initial elevation of transaminases or other adverse effects. To our knowledge, this is the first case reported where OA was administered via a central line. This type of administration is not contraindicated, but it is not specifically contemplated or recommended. It is unknown whether central line administration could have any implications for transduction efficiency and immunogenicity. Future studies should clarify these aspects, as each gene therapy has a specific optimal dose recorded that depends on the site and route of administration of the drug, the AAV variant and the transgene.

Long-Term Comparative Efficacy and Safety of Risdiplam and Nusinersen in Children with Type 1 Spinal Muscular Atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type 1 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 2 years. 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. METHODS: The long-term efficacy and safety of risdiplam versus nusinersen in children with type 1 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 36 months of follow-up. RESULTS: Children with type 1 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, Module 2 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. CONCLUSION: Long-term data supported risdiplam as a superior alternative to nusinersen in children with type 1 SMA. Video abstract available for this article. Video abstract (MP4 184542 KB).

Risdiplam and nusinersen are two approved treatments for patients with type 1 spinal muscular atrophy (SMA). There are currently no head-to-head trials that compare the outcomes of these treatments in patients. This study conducted a statistical comparison of the efficacy and safety of risdiplam and nusinersen in children with type 1 SMA who received treatment for at least 36 months. Risdiplam data were collected from 58 children who participated in the FIREFISH trial (NCT02913482). Published combined data were collected from 81 children treated with nusinersen who participated in the ENDEAR (NCT02193074) and SHINE (NCT02594124) trials. Outcomes from the two studies were compared using matching-adjusted indirect comparison (MAIC) methodology. MAIC adjusts for differences in baseline characteristics between patients in two trials to make the populations more similar and reduce bias in the comparison. Results suggested that children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death and an 81% reduction in the rate of death or permanent ventilation compared with children treated with nusinersen. With risdiplam, children also had a higher rate of achieving motor function responses, and a longer time to the first serious adverse event compared with children treated with nusinersen. These results support risdiplam as a superior alternative to nusinersen in children with type 1 SMA over 36 months of follow-up. Access to long-term data beyond 36 months would allow for additional indirect comparisons between SMA treatments. These comparisons are key to guiding treatment decision-making in the absence of head-to-head trials.

From data to discovery: AI-guided analysis of disease-relevant molecules in spinal muscular atrophy (SMA).

Spinal Muscular Atrophy is caused by partial loss of survival of motoneuron (SMN) protein expression. The numerous interaction partners and mechanisms influenced by SMN loss result in a complex disease. Current treatments restore SMN protein levels to a certain extent, but do not cure all symptoms. The prolonged survival of patients creates an increasing need for a better understanding of SMA. Although many SMN-protein interactions, dysregulated pathways, and organ phenotypes are known, the connections among them remain largely unexplored. Monogenic diseases are ideal examples for the exploration of cause-and-effect relationships to create a network describing the disease-context. Machine learning tools can utilize such knowledge to analyze similarities between disease-relevant molecules and molecules not described in the disease so far. We used an artificial intelligence-based algorithm to predict new genes of interest. The transcriptional regulation of 8 out of 13 molecules selected from the predicted set were successfully validated in an SMA mouse model. This bioinformatic approach, using the given experimental knowledge for relevance predictions, enhances efficient targeted research in SMA and potentially in other disease settings.

Gene therapy: principles, challenges and use in clinical practice.

INTRODUCTION: Gene therapy is an emerging topic in medicine. The first products have already been licensed in the European Union for the treatment of immune deficiency, spinal muscular atrophy, hemophilia, retinal dystrophy, a rare neurotransmitter disorder and some hematological cancers, while many more are being assessed in preclinical and clinical trials. OBJECTIVE: The purpose of this review is to provide an overview of the core principles of gene therapy along with information on challenges and risks. Benefits, adverse effects and potential risks are illustrated based on the examples of hemophilia and spinal muscular atrophy. RESULTS: At present, in-vitro and in-vivo gene addition or gene augmentation is the most commonly established type of gene therapy. More recently, more sophisticated and precise approaches such as in situ gene editing have moved into focus. However, all types of gene therapy require long-term observation of treated patients to ensure safety, efficacy, predictability and durability. Important safety concerns include immune reactions to the vector, the foreign DNA or the new protein resulting from gene therapy, and a remaining low cancer risk based on insertional mutagenesis. Ethical and regulatory issues need to be addressed, and new reimbursement models are called for to ease the financial burden that this new treatment poses for the health care system. CONCLUSION: Gene therapy holds great promise for considerable improvement or even cure of genetic diseases with serious clinical consequences. However, a number of questions and issues need to be clarified to ensure broad accessibility of safe and efficacious products.