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NMD670 is an inhibitor of skeletal muscle-specific chloride channel protein 1 (ClC-1) that enhances neuromuscular transmission and is being developed for the treatment of neuromuscular diseases, including myasthenia gravis (MG), in which neuromuscular junction (NMJ) transmission is impaired. Despite available treatments, MG patients struggle with symptoms of prominent muscle weakness and fatigue. In a recent phase 1 proof-of-mechanism study of NMD670 in 12 MG patients with mild symptoms, a single dose of NMD670 led to significant and clinically meaningful improvements as assessed with the Quantitative MG (QMG) score. Furthermore, NMD670 was shown to be safe and well tolerated thus supporting further clinical development in MG (Sci Transl Med. 2024). Therefore, a dose-finding study in adult patients with MG who have antibodies against Muscle Specific Kinase (MuSK) or the Acetylcholine Receptor (AchR) is planned to start in 2024. The aim of this study is to evaluate the efficacy and safety of 3 dose levels of NMD670, administered twice a day for 21 days vs. placebo. Male and female patients, aged 18-75 years, diagnosed with MG and with a Myasthenia Gravis Foundation of America (MGFA) class II-IV, a QMG score of 11 or more and an MG-Activities of Daily-Living score of 6 or more at screening are planned to be enrolled at 40 sites across Europe and North America. Endpoints of this study include changes in the QMG total score MG-ADL, MG Composite (MGC), MG Quality of Life 15 revised (QOL15r), and Neuro Qol Fatigue Short Form total scores. A more detailed study design, target population, and other key updates will be provided by NMD Pharma A/S at the 29th Annual Congress of the World Muscle Society in October 2024. [ABSTRACT FROM AUTHOR]

NMD670, developed by NMD Pharma, is a first-in-class neuromuscular transmission enhancer targeting the skeletal muscle chloride channel 1 (ClC-1). It is designed to address neuromuscular disorders characterized by impaired neuromuscular transmission. Partial ClC-1 inhibition by NMD670 has recently been shown to improve NMJ transmission in preclinical models of myasthenia gravis and Charcot-Marie-Tooth and symptoms in patients with myasthenia gravis. Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy leading to muscle weakness and fatigue, with no approved treatments and significant unmet medical needs. Emerging data from recent studies, including an observational study (NCT04980807) by NMD Pharma, suggest that NMJ transmission contributes to symptoms of weakness and fatigue in CMT. Correlations were observed between jitter, blocking, and impaired strength, mobility, balance, and endurance in CMT patients. Consequently, NMD670 emerges as a promising candidate for CMT treatment, prompting the initiation of the SYNAPSE-CMT study. SYNAPSE-CMT is a phase 2 study aiming to assess the efficacy, safety, and tolerability of NMD670 in ambulatory adults with CMT. Approximately 80 participants diagnosed with CMT type 1 and 2 will be randomized across 19 sites in North America and Europe. Participants will receive NMD670 or placebo twice daily for 21 days. Endpoints include the 6-minute walk test, the 10-meter walk/run test, the timed up-and-go test, and the CMT-FOM composite assessments comparing the effects of NMD670 to placebo. Enrollment of the first subject is planned for 2024. Detailed study design, target population, and updates will be provided by NMD Pharma at the 29th Annual Congress of the World Muscle Society in October 2024. [ABSTRACT FROM AUTHOR]

We described an unusual clinical phenotype of three siblings, one male and two females aged 25, 24 and 16 years respectively, of first-degree cousins Moroccan parents; another brother and sister were not affected. At the age of three years for the young sister and six years for the two older, they presented with acute appearance of an inflammatory clinical phenotype characterized by joint stiffness, redness and pain, associated with rapidly evolution of proximal muscle weakness leading to difficulties in walking, arising from the floor and running. CK blood levels were normal. The diagnosis of juvenile polyarthritis was proposed and the joints inflammatory phenotype successfully treated with TNF α inhibitor. A muscle biopsy was performed in the oldest and the youngest at 3 and 7 years respectively from the onset of symptoms. The biopsy revealed a granulomatous myositis with CD68 and CD3 positive inflammatory infiltrate and muscular necrosis. Mycobacterium tuberculosis and non tuberculosis were excluded by PCR as were other sporadic causes of granulomatous myositis such as sarcoidosis, infection and neoplastic diseases. Thirteen to nineteen years after the symptoms, all three siblings show joint contractures especially in proximal limb segment as well as in the shoulders, hips and knees. Atrophy of the distal muscles of the lower limbs is clearly noticeable, without muscle weakness. Recently, the younger sister have been investigated by muscular MRI that showed an intramuscular edema of the thigh and twins muscles. Recently, mutations in different genes associated with Mendelian transmission of dysimmunity disease have been demonstrated, and it is likely that this until now unreported association belongs to this emerging group of diseases. [ABSTRACT FROM AUTHOR]

Abstract: Several studies have reported abnormalities in muscle histology of cricopharyngeal muscle (CPM) from healthy donors. However, very little is known concerning the morphological structure of this muscle that, together with the elevator eyelid muscle, represents the main muscular targets of oculopharyngeal muscular dystrophy (OPMD). OPMD is a late onset autosomal dominant inherited dystrophy due to an expansion of GCG repeats in the coding region of the ubiquitously expressed PABPN1 gene. In OPMD patients, progressive involvement of these muscles leads to dysphagia and ptosis. In this study, CPM biopsies from seven OPMD patients and five healthy individuals were investigated by histological and histochemical approaches as well as by quantitative RT-PCR analysis. Surprisingly, histological features were similar between OPMD patients and control subjects without any correlation with age: in addition to the extensive fibro-connective substitution (30–40%), all CPM showed a high variability in muscle fibre size, rimmed vacuoles, internalized nuclei, ’ragged red’ fibres and split fibres. In CPM, a higher number of satellite cells were observed as compared to other muscle, with a significant difference between control and OPMD (7% versus 12% respectively), further confirmed by increased Pax7 mRNA levels. To further evaluate the regenerative capacity of these satellite cells, OPMD and control cells were transplanted into cryodamaged tibialis anterior muscle of immunodeficient mice. This study will help us to understand the defects in muscle fibres regeneration in OPMD. Analyses on CPM are now being extended to a less affected muscle, the sternocleidomastoideus muscle (SCM) from OPMD and healthy individuals to improve our understanding of the pathophysiology of OPMD. [Copyright &y& Elsevier]

X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disorder caused by mutations in the myotubularin (MTM1) gene, affecting 1:50000 male births. The clinical severity varies, however the need for ventilatory support is often inevitable. At present, no approved therapies are available for XLMTM. Patient management is mainly supportive. A first MTM1 gene replacement therapy tested in a clinical trial showed notable improvements on ventilator dependence and motor function but raised serious safety concerns. Forty patients have been enrolled in our European prospective natural history study of patients with XL-MTM designed to characterize the disease course by using standardized evaluations adjusted for age, ambulatory and respiratory status. At 3-year follow-up, data were available for 26 patients (65%) with a mean age of 14.3 (min 3.4, max 53.8) years. Drop-outs were due to loss to follow-up (n=1), death (n=1) and early withdrawal from the study (n=3). Nineteen percent (5/26) of patients were under the age of 6 years old. Among non-ambulant patients at baseline (n=19), only 1 acquired the ability to walk during the study. Respiratory function, strength and motor function did not statistically change. Muscle strength measured by MyoPinch and MyoGrip showed a mean decline of -1,04 kg (n=20) and -0.33kg (n=20) respectively. MFM D1 showed the most important decline of -2.98% at 36 months. Nine patients presented with a mean increase of grip strength of 1.5kg (SD 4.18) (n=13). Ten patients showed a mean increase of the pinch strength of 0.16kg (SD 0.71) (n=14). Correlation data will be presented. This first multicentric longitudinal natural history in all types of patients with XL-MTM demonstrates clearly that patients experience a decline over years that can be reliably measured. We have identified several strength-, functional and respiratory outcomes that can be used to build robust clinical trials in this population. [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 approved in more than 70 countries worldwide. JEWELFISH (NCT03032172) is a multicenter, open-label study that assesses the safety, tolerability and pharmacokinetic/pharmacodynamic (PD) relationship of daily risdiplam in non-treatment-naïve patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®). The enrolled population (N=174) included a broad range of ages (1–60 years), SMA types (1–3), SMN2 copy numbers (1–4) and motor functions (non-sitters, sitters and walkers). We previously presented safety data from 173 patients (data cut-off: 29 January 2021) who received risdiplam for up to 47 months. One patient withdrew from the study at baseline; of the remaining patients, 13 previously received RG7800, 76 received nusinersen, 70 received olesoxime and 14 received onasemnogene abeparvovec. Risdiplam treatment led to a rapid and sustained >2-fold increase in SMN protein levels in blood compared with baseline levels (data cut-off: 29 January 2021), consistent with PD data from the SUNFISH (NCT02908685) study of treatment-naïve patients with Types 2/3 SMA. No drug-related safety findings leading to withdrawal were reported for any patients exposed to risdiplam in JEWELFISH at month 12. The risdiplam safety profile was consistent with the safety profile observed in risdiplam treatment-naïve trials. Here we will present the month 24 results from JEWELFISH for the first time. The JEWELFISH study is ongoing at sites across Europe and the USA and is providing important data on the safety and PD of risdiplam in a broad population of non-treatment-naïve patients with SMA. [ABSTRACT FROM AUTHOR]

The regenerative capacity of skeletal muscle will depend on the number of available satellite cells and their proliferative capacity. We have measured both parameters in ageing, and have shown that although the proliferative capacity of satellite cells is decreasing during muscle growth, it then stabilizes in the adult, whereas the number of satellite cells decreases during ageing. We have also developed a model to evaluate the regenerative capacity of human satellite cells by implantation into regenerating muscles of immunodeficient mice. Using telomere measurements, we have shown that the proliferative capacity of satellite cells is dramatically decreased in muscle dystrophies, thus hampering the possibilities of autologous cell therapy. Immortalization by telomerase was unsuccessful, and we currently investigate the factors involved in cell cycle exits in human myoblasts. We have also observed that insulin-like growth factor-1 (IGF-1), a factor known to provoke hypertrophy, does not increase the proliferative potential of satellite cells, which suggests that hypertrophy is provoked by increasing the number of satellite cells engaged in differentiation, thus possibly decreasing the compartment of reserve cells. We conclude that autologous cell therapy can be applied to specific targets when there is a source of satellite cells which is not yet exhausted. This is the case of Oculo–Pharyngeal Muscular Dystrophy (OPMD), a late onset muscular dystrophy, and we participate to a clinical trial using autologous satellite cells isolated from muscles spared by the disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented describing the coexistence of an original de novo missense mutation of the MFN2 gene and an inherited dominant GDAP1 mutation in a 5-year-old boy with severe early-onset axonal Charcot-Marie-Tooth disease (CMT).

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant inherited, slow progressing, late onset degenerative muscular disorder where a small group of specific muscles – pharyngeal and eyelid muscles – are primarily affected, leading to dysphagia and ptosis. Its genetic basis is a trinucleotide repeat expansion ranging from (GCG)8 to (GCG)13 in the N-terminus polyalanine domain of the poly(A) binding protein nuclear 1 (PABPN1) gene. Mutated expanded PABPN1 protein accumulates as insoluble nuclear inclusions in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and in the regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Using a Drosophila model of OPMD, we found that OPMD pathogenesis depends on affected poly(A) tail length regulation of specific mRNAs. We identified a set of mRNAs encoding mitochondrial proteins that are down-regulated during OPMD progression. Reduced levels of these mRNAs correlate with their shortened poly(A) tails. Partial rescue of the levels of these mRNAs when deadenylation is decreased using a deadenylase mutant improves mitochondrial function and reduces muscle weakness. Interestingly, the down-regulation of these mRNAs already occurs in the earliest stages of disease progression, indicating that this defect is one of the first molecular defects in OPMD. Importantly, the down-regulation of mRNAs encoding mitochondrial proteins has been validated in a transgenic mouse model of OPMD. Moreover, a proteomic approach has also validated the down-regulation of mitochondrial proteins in clinically nonaffected muscles of OPMD patients. We propose a model where one of the primary defect in OPMD corresponds to defective poly(A) tail regulation of specific mRNAs encoding mitochondrial proteins, leading to decreased synthesis of mitochondrial proteins and defective mitochondrial activity. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease for which treatments are being developed. There is a need to define reliable and reproducible criteria to evaluate neuromuscular function in order to assess their effects. The main aim of our study consists of a follow-up of the natural history of DM1 patients over 3 years. Here, baseline values for the 6-min walk distance (6MWD), the lower limb muscle strength and balance measured by the movement rate of the centre of foot pressure on a force plateform are compared between patients and age- and sex-matched healthy controls. DM1 patients and healthy controls (10 females and 7 males between 26 and 49 years old in each group) of similar mean height and weight were compared. The 6MWD in percentage of predicted value was significantly reduced in DM1 patients by about 50% (Mann Whitney, p < 0.001). No significant difference in balance was found but ankle muscle strength weakness could account for the reduced 6MWD. Indeed, no significant difference of the movement rate of the centre of foot pressure was observed with age or between patients and healthy subjects (ANCOVA) but significant decreases in ankle dorsi- and plantarflexion strength measured by a homemade ankle dynamometer were detected between patients and healthy subjects (Mann Whitney p < 0.001 and p < 0.01, respectively). Balance defect, however, seems affected for the weakest ankle muscle strengths. Moreover, the 6MWD was positively correlated to ankle dorsiflexion (rho 0.671, p < 0.01) and plantarflexion in patients (rho 0.637, p < 0.01), while it was positively correlated to plantarflexion only in healthy controls (rho 0.586, p < 0.05). No significant difference in hip flexion, knee extension, ankle dorsiflexion and big toe extension assessed by hand-held dynamometry could be evidenced between patients and healthy controls. Walking ability is thus mainly affected by weakness in ankle dorsi- and plantarflexion when measured by appropriate method. [ABSTRACT FROM AUTHOR]

Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluate efficacy of new treatments in non-ambulant patients. Adequate outcome measures are scarce for patients who have lost ambulation. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures on a short term period are lacking. We report here the results of a one-year multicenter study using specifically designed tools to assess grip and key pinch strength and hand function in wheelchair bound patients. Our study recruited 53 non-ambulant patients with Duchenne muscular atrophy aged 17.1 ± 4.8 years (range: 9–28.1 years). The Brooke functional score was 4.6 ± 1.1. The average forced vital capacity was 44.5 % and nineteen patients used non-invasive ventilation. Patients were assessed at baseline, 6 months and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch and MoviPlate). Our study confirmed the preliminary data previously reported regarding feasibility, reliability of the MyoSet and correlation between the distal strength and clinical variables. We demonstrated that the use of sensitive dynamometers could capture a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. [ABSTRACT FROM AUTHOR]