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OFELIA (NCT05073133), a phase 4, open-label, multicenter study conducted in Latin America, assessed safety and efficacy of single-dose intravenous onasemnogene abeparvovec (OA) for patients with spinal muscular atrophy (SMA) weighing ≤17 kg and ≤24 months old over 18 months post-infusion. Primary endpoint was safety, measured by treatment-emergent adverse events (TEAEs), serious TEAEs, adverse events of special interest (AESI), and hematology/laboratory changes. Secondary endpoint was efficacy, measured by WHO MGRS motor milestone achievement. Data were summarized descriptively. Sixteen patients were enrolled; three (19%) were previously treated with nusinersen. At dosing, median (range) age was 17.88 (3.95–23.75) months and weight was 8.35 (6.10–12.10) kg. Most patients had SMA type 1 (n=10; 62.5%) and two (n=8; 50.0%) or three (n=8; 50.0%) SMN2 copies. Safety was consistent with previous studies with OA. Eleven patients (68.8%) experienced serious TEAEs. Twelve patients (75.0%) experienced AESI: 11 (91.7%) hepatotoxicity, 5 (41.7%) thrombocytopenia, and 2 (16.7%) thrombotic microangiopathy (TMA). Transaminase elevations (n=2/16; 12.5%) were asymptomatic; troponin elevations (n=6/8; 75.0%) were isolated and without clinical relevance. Two (12.5%) deaths occurred: one due to AESI of TMA (related to treatment per investigator); the second death was not related to treatment. Most patients achieved WHO MGRS motor milestones by 18 months of follow-up (up to 3 years old for most patients): sitting without support (n=10/12; 83.3%), crawling (n=3/12; 25.0%), standing with assistance (n=7/12; 58.3%), walking with assistance (n=2/12; 16.7%), standing alone (n=3/12; 25.0%), and walking alone (n=1/12; 8.3%). OFELIA confirms that OA is safe and efficacious for older, heavier patients with SMA and for patients from different geographic locations than previously studied. Most patients demonstrated maintenance or improvement of motor milestones up to 18 months post-treatment. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare disease characterized by progressive loss of motor neurons. The most common form of SMA (5q-SMA), classified into subtypes, according to the age of onset and the maximum motor function achieved. Nusinersen is a disease modifying treatment (DMT), incorporated free of charge into the Brazilian Unified National Health System (SUS) for the treatment of subtype 1 of the disease, in 2019. In 2021, the treatment was expanded to 5q-SMA subtype 2. This is a cross-sectional observational study aimed to characterize the clinical characteristics and access to DMT from patients with 5q-SMA types 2 and 3 in references centers from the SUS. Patients with 5q-SMA types 2 and 3, both sexes from 9 national reference centers were included between 2020 to 2021, independent of DMT treatment. A total of 155 patients were included, 76 of subtype 2 and 79 of subtype 3. For subtype 2, 45% sit stable, 11% stand with support, 78% have scoliosis and 39 have access to Nusinersen and 37 without access the DMT. As for subtype 3, 43% sit stably, 13% stand with support, 34% walk independently, 66% have scoliosis and 21 have access to Nusinersen and 58 without access to DMT. In the Brazilian Public Health System, the SMA patients has poorly access to DMT for 5q-SMA subtype treatment with relevant clinical impacts in long-term. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare disease characterized by progressive loss of motor neurons located in the anterior horn of the spinal cord and brainstem, leading to progressive muscle atrophy and weakness. The most common form of SMA (5q SMA) is caused by bi-allelic mutations in the SMN1 gene on chromosome 5q13.2, classified into subtypes, according to the age of onset and the maximum motor function achieved. The journey to diagnosis can last for years and have a wide and significant impact on patients' lives. This study aims to map the time interval between the appearance of the first signs and symptoms to lived achievement of the 5q-SMA diagnosis using a genetic report in Latin American patients with 5q-SMA. In this study the data analysis in a multicenter clinical registry for SMA disease include patients with SMA 5q types 1, 2, 3 and 4 of all ages and both sexes, treated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Uruguay). Currently 361 participants were included, with an average age of 13.7 (years), with 59.3% females and 40.7% males. Results show subtype 2, 158 (43.8%) constitutes the largest number of participants in this study, followed by subtypes 3(38.0%) and 1, 114 (31.5%). To date, 245 (67.9%) use or have had access to disease modifying therapy for SMA and 116 (32.1%) have never had access to therapies. Knowing the reality of the patients' journey is relevant for greater assertiveness in the clinical management of the disease and management of access to treatments that modify the course of the disease. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a genetic rare disease characterized by progressive loss of motor neurons located in the anterior horn of the spinal cord and brainstem, leading to progressive muscle atrophy and weakness. The most common form of SMA (5q-SMA) classified into subtypes, according to the age of onset and the maximum motor function achieved. This study is an international multicenter clinical Registry for SMA diseases (LATAM RegistrAme study NCT05475691) that includes patients with 5q-SMA types 1, 2, 3 and 4 of all ages and both sexes, treated at reference centers in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay). The average time of appearance of the first signs and symptoms, the average time of illness, and the time interval between the appearance of the first signs and symptoms until obtaining the confirmatory genetic diagnosis of 5q-SMA and the clinical evolution over the course of the study will be analyzed. Currently, the study already has 361 patients included (Argentina: 63; Brazil: 180; Chile: 35; Colombia: 54; Mexico: 20 and Uruguay: 7). The SMA subtype 2 constitutes the largest number of participants included in the study, followed by subtypes 3 and 1. The mean time for first signs and symptoms was one month of life. The mean time to reach the confirmatory molecular report of 5q-SMA varies greatly across countries. Analyzing the reality of how long it takes for these patients to arrive at confirmation of the genetic diagnosis of 5q-SMA is of great relevance. Diagnostic confirmation is fundamental for greater assertiveness in the clinical management of the disease and access to treatments that modify the course of the disease (DMTs). Knowing the time profile of patients with 5q-SMA diagnosis in Latin America is scarce; however, the LATAM RegistrAME is the first Registry study to improve the knowledge of SMA clinical management in Latin-America. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XL-MTM) is a rare and often lethal congenital myopathy, clinically characterized by muscle weakness. Its underlying molecular mechanisms remain incompletely understood. As myosin has been implicated in the pathophysiology of other forms of congenital myopathies, in the present study, we aimed to define whether muscle myosin is dysfunctional in the context of XL-MTM. For that, we used muscle tissue from human patients and a canine model. We isolated individual muscle fibres from these two species and performed loaded Mant-ATP chase experiments. Our preliminary results indicate a shift of myosin metabolic/biochemical states towards highly energy-consuming conformations in human and canine XL-MTM. Subsequently, to reverse this alteration potentially contributing to muscle fatigue, we investigated the effects of an ATP-conserving drug targeting myosin, mavacamten, using a well-defined mouse model of XL-MTM lacking myotubularin. The results are currently being analysed and include histology as well as untargeted global proteomics. Potentially, taken together, these data will lead to a better understanding of XL-MTM and the potency of myosin as a drug target. [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre‑mRNA splicing modifier that has been widely approved for the treatment of spinal muscular atrophy (SMA). RAINBOWFISH (NCT03779334) is a global, open-label, single-arm, multicentre, Phase 2 study assessing the efficacy, safety and pharmacokinetics/pharmacodynamics of risdiplam in infants with genetically diagnosed and presymptomatic SMA from birth to 6 weeks of age (at first dose), regardless of SMN2 copy number. The study enrolled 26 infants: eight infants had two SMN2 copies, 13 infants had three SMN2 copies and five infants had ≥4 SMN2 copies. The primary efficacy (PE) population (n=5) had two SMN2 copies and baseline compound muscle action potential (CMAP) amplitudes ≥1.5mV. Drug dosage was adjusted to achieve a target exposure of approximately 2,000 ng∙ hr/mL. The primary endpoint was met after 12 months of risdiplam treatment with 4/5 (80%) infants in the PE population able to sit without support for ≥5 seconds (Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition [BSID-III]). Irrespective of CMAP amplitude, 7/8 infants with two SMN2 copies were able to sit without support for ≥30 seconds (BSID‑III Item 26), including all infants with CMAP amplitude <1.5 mV (n=3). Out of 26 infants, 24 (92%) were able to sit without support, 13 (50%) were able to stand unaided and 12 (46%) were able to walk independently at Month 12, as assessed by the Hammersmith Infant Neurological Examination, Module 2. At Month 12, all infants were alive without permanent ventilation, maintained their swallowing and feeding abilities and no adverse events (AEs) led to withdrawal or treatment discontinuation. Most AEs were not considered treatment-related and resolved over time. One infant met the criteria for development of clinically manifested SMA. Here we report, for the first-time, the 2-year efficacy and safety data from RAINBOWFISH. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants at TK2 lead to a severe and progressive and specific myopathy (TK2d). In a scenario of a potential supplementation therapy that changes the natural history of the disease, it is urgent to increase suspicion and accelerate diagnosis. We described the clinical characterization of 31 TK2d patients from several centers across Brazil. Genotype-phenotype correlation was performed for recurrent and novel variants. Motor and respiratory assessments were systematically performed in 10 patients, three of whom were receiving the nucleosides reposition therapy. Eight patients with the infantile form, 18 with childhood form and 5 with late-onset form were described. Extramuscular features were present in 30% of the cohort. Neuropathy and encephalopathy were clinically predominant for some patients. Four variants were recurrent, and one was novel, allowing genotype-phenotype correlations. T108M patients presented a milder presentation compared to the H121N group. R183T was associated with peripheral nerve involvement and c.536_538+8del with encephalomyopathic involvement. A two-year follow-up of three patients showed decreased motor, bulbar, and respiratory function, compared to a dramatic improvement in treated patients. TK2d is a very debilitating disease. Early diagnosis is essential in order to change the natural history of the disease and reduce the high mortality and morbidity rates. High diagnostic suspicion is imperative, and extramuscular involvement might play an important role for diagnostic strategies, starting with the inclusion of the TK2d in the differential diagnosis for neuropathies and epilepsy. Despite the higher mortality rates among infantile-patients, childhood-onset disease is also a debilitating and progressive disease. And the nucleosides reposition was well tolerated and benefic for the patients presented here. [ABSTRACT FROM AUTHOR]

The Motor Unit Number Index (MUNIX) has emerged as a more sensitive biomarker for detecting motor unit loss in 5q-spinal muscular atrophy (SMA) compared to compound muscle action potential (CMAP). Recent studies have shown correlations between MUNIX values of various muscles and motor scales used to assess disease progression and treatment response. Objective: This study is an investigation of the feasibility of MUNIX as a biomarker for disease progression in SMA types 3 and 4 treated with nusinersen. A four-year study involved 20 patients diagnosed with SMA types 3 and 4, ten treated with nusinersen and ten non-treated. Patients underwent evaluations using the Hammersmith Functional Motor Scale Expanded (HFMSE), the 6-minute walk test (6MWT), and assessments of CMAP and MUNIX in the abductor policis brevis (APB), adductor digiti minimi (ADM), and tibialis anterior (TA) muscles. A significant change was observed between the first and fourth years in CMAP values of the ADM muscle (p=0.012) in treated patients. In contrast, untreated patients experienced a significant reduction in mean CMAP values of the TA (p=0.015). Significant decreases in mean MUNIX values were found only in untreated patients, in the ADM (p=0.022) and TA (p<0.001). Treated patients experienced an average increase of 24.9 points in the MUNIX of the ADM (p=0.024) compared to non-treated patients. CMAP and MUNIX values for the TA muscle correlated with HFMSE scale results. The MUNIX values of ADM and TA muscles are biomarkers for disease progression in 5q-SMA types 3 and 4 over a four-year follow-up period. Despite a significant increase in ADM CMAP values among treated patients, only ADM MUNIX could identify motor unit loss in untreated patients. Furthermore, MUNIX values remained stable among treated patients over the four-year follow-up period. [ABSTRACT FROM AUTHOR]