scholarly journals Spinal Muscular Atrophy: The Use of Functional Motor Scales in the Era of Disease-Modifying Treatment

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110087
Author(s):  
Katarzyna Pierzchlewicz ◽  
Izabela Kępa ◽  
Jacek Podogrodzki ◽  
Katarzyna Kotulska
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Muscular Atrophy ◽  
Age Groups ◽  
Ventilatory Support ◽  
Gene Replacement ◽  
Motor Disability ◽  
Smn2 Gene ◽  
Disease Modifying ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a genetic condition characterized by progressive motoneuron loss. Infants affected by SMA type 1 do not gain developmental milestones and acutely decline, requiring ventilatory support. Several scales are used to assess motor disability and its progression in SMA. Recently, 3 disease-modifying therapies have been approved for SMA patients: nusinersen, an intrathecal antisense oligonucleotide enhancing SMN protein production by the SMN2 gene, risdiplam, also influencing the SMN2 gene to stimulate SMN production but administered orally, and onasemnogene abeparvovec-xioi, an SMN1 gene replacement therapy. Thus, the functional scales should now be applicable for patients improving their motor function over time to assess treatment efficacy. In this paper, we compare different functional scales used in SMA patients. Their usefulness in different SMA types, age groups, and feasibility in daily clinical practice is described below. Some changes in motor function assessments in SMA are also suggested.

scholarly journals Small-molecule flunarizine increases SMN protein in nuclear Cajal bodies and motor function in a mouse model of spinal muscular atrophy

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Delphine Sapaly ◽  
Matthieu Dos Santos ◽  
Perrine Delers ◽  
Olivier Biondi ◽  
Gwendoline Quérol ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Small Molecule ◽  
Muscular Atrophy ◽  
Cajal Bodies ◽  
Smn Protein

Treatment strategies for spinal muscular atrophy

2010 ◽  
Vol 1 (4) ◽  
Author(s):  
Heidi Fuller ◽  
Marija Barišić ◽  
Đurđica Šešo-Šimić ◽  
Tea Špeljko ◽  
Glenn Morris ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Treatment Strategies ◽  
Transcript Level ◽  
Survival Motor Neuron ◽  
Current Status ◽  
Protein Levels ◽  
Smn2 Gene ◽  
Smn Protein ◽  
Cell And Gene Therapy

AbstractProgress in understanding the genetic basis and pathophysiology of spinal muscular atrophy (SMA), along with continuous efforts in finding a way to increase survival motor neuron (SMN) protein levels have resulted in several strategies that have been proposed as potential directions for efficient drug development. Here we provide an overview on the current status of the following approaches: 1) activation of SMN2 gene and increasing full length SMN2 transcript level, 2) modulating SMN2 splicing, 3) stabilizing SMN mRNA and SMN protein, 4) development of neurotrophic, neuroprotective and anabolic compounds and 5) stem cell and gene therapy. The new preclinical advances warrant a cautious optimism for emergence of an effective treatment in the very near future.

Effect of Discontinuation of Nusinersen Treatment in Long-Standing SMA3

2021 ◽  
pp. 1-6
Author(s):  
Miriam Hiebeler ◽  
Angela Abicht ◽  
Peter Reilich ◽  
Maggie C. Walter
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Rna Splicing ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Spinal Muscular Atrophy Type ◽  
Protein Levels ◽  
Discontinuation Of Treatment ◽  
Smn Protein ◽  
Treatment Onset

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disease leading to ongoing degeneration of anterior horn cells in the spinal cord. Nusinersen is the first approved treatment for the condition, an intrathecally administered antisense oligonucleotide. It modulates pre-RNA splicing of the SMN2 gene and increases full-length SMN protein expression, thereby increasing SMN protein levels. The benefit of Nusinersen for patients with spinal muscular atrophy type 3 (SMA3) has recently been shown in several real-world cohorts. Objective: We aim to elucidate not only the effect of therapy with Nusinersen, but the development of the disease course after discontinuation of treatment. To our knowledge, there are so far no reports on the effects of Nusinersen discontinuation. Methods: We report on a 45-year-old female patient with genetically confirmed SMA3 and a disease duration of 40 years prior to treatment onset. Results: The patient was non-ambulantory, best motor function at treatment onset was holding arms with support, reflected in MRC of 3/5 in upper limbs. After having received Nusinersen for 11 months without complications, the patient showed improvement in motor functions, as measured by hand grip measurement (HGS), Hammersmith Functional Rating Scale Expanded (HFMSE), and Revised Upper Limb Module (RULM). Due to worsening of a pre-existing anxiety disorder, treatment was discontinued after six injections. Sixteen months later, progression of the disease became evident with worsening of HFMSE and RULM scores, while hand strength remained stable. Conclusion: Treatment with Nusinersen in SMA3 improves motor function in longstanding disease even in clinically advanced stages; however, after discontinuation of treatment, further progression mirroring the natural history of the disease is anticipated.

scholarly journals New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

2020 ◽  
Vol 9 (7) ◽  
pp. 2222 ◽  
Author(s):  
Sonia Messina ◽  
Maria Sframeli
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Respiratory Muscles ◽  
Gene Replacement ◽  
Survival Motor Neuron ◽  
Significant Disability ◽  
New Challenges ◽  
Smn Protein ◽  
New Treatments

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies.

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Science ◽  
2014 ◽  
Vol 345 (6197) ◽  
pp. 688-693 ◽  
Author(s):  
Nikolai A. Naryshkin ◽  
Marla Weetall ◽  
Amal Dakka ◽  
Jana Narasimhan ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Messenger Rna ◽  
High Selectivity ◽  
Therapeutic Potential ◽  
Muscular Atrophy ◽  
Chemical Screening ◽  
Protein Levels ◽  
Smn Protein ◽  
Survival Of Motor Neuron

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

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