RARE DISEASE
Spinal muscular atrophy with respiratory distress type 2
Spinal muscular atrophy with respiratory distress type 2
Spinal muscular atrophy with respiratory distress type 2
Synonyms: Diaphragmatic spinal muscular atrophy type 2, SMARD2, Severe infantile axonal neuropathy with respiratory failure type 2, X-linked spinal muscular atrophy with respiratory distress
Synonyms: Diaphragmatic spinal muscular atrophy type 2, SMARD2, Severe infantile axonal neuropathy with respiratory failure type 2, X-linked spinal muscular atrophy with respiratory distress
Synonyms: Diaphragmatic spinal muscular atrophy type 2, SMARD2, Severe infantile axonal neuropathy with respiratory failure type 2, X-linked spinal muscular atrophy with respiratory distress
Drug discovery
0
drugs
With orphan designations
Overview
Spinal Muscular Atrophy with Respiratory Distress Type 2 (SMARD2) is a rare, genetic motor neuron disorder characterized by early-onset (<2 years) respiratory failure due to diaphragmatic paralysis, distal muscle weakness, axial hypotonia, and joint contractures. It is caused by mutations in the IGHMBP2 gene, distinct from SMA-associated SMN1 mutations. Unlike typical SMA, SMARD2 involves predominant diaphragm dysfunction and distal muscle onset [1][5].
Burden
Mortality: High risk of early death from respiratory failure without intervention [1][13].
Morbidity: Progressive muscle weakness, recurrent pneumonias, and lifelong ventilator dependence in 60-80% of cases [9][13].
Healthcare utilization: Frequent hospitalizations, prolonged ICU stays, and high caregiver burden due to complex respiratory/functional needs [4][13].
Therapies
Supportive care: Non-invasive ventilation (NIV), tracheostomy, and airway clearance techniques for respiratory failure [1][9][13].
Multidisciplinary management: Physical/occupational therapy for contractures, nutritional support (gastrostomy if needed), and scoliosis monitoring [4][8].
Experimental approaches: Limited evidence for gene therapy; focus remains on SMN-targeted therapies (e.g., nusinersen) for overlapping SMA phenotypes [3][7].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
144 drug discovery papers about Spinal muscular atrophy with respiratory distress type 2, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
144 drug discovery papers about Spinal muscular atrophy with respiratory distress type 2, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
oligonucleotides
2024-03-01 | Exploration of adverse events associated with risdiplam use: Retrospective cases from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database
Risdiplam is a new drug for treating spinal muscular atrophy (SMA). However, pharmacovigilance analyses are necessary to objectively evaluate its safety—a crucial step in preventing severe adverse events (AEs). Accordingly, the primary objective of the current study was to examine the AEs associated with risdiplam use based on real-world data obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. More specifically, we examined incidents reported between the third quarter of 2020 and the second quarter of 2023. The imbalance of risdiplam-related AEs was evaluated by computing the reporting odds ratio. A total of 5,406,334 reports were thoroughly reviewed. By removing duplicate reports, we identified 1588 reports in which risdiplam was the main suspected drug whose use was accompanied by 3470 associated AEs. Among the included AEs, 703 were categorized as serious and 885 as non-serious. Risdiplam use induced AEs across 18 organ systems, resulting in 130 positive signals. Notably, we detected new AE signals, including cardiac arrest, nephrolithiasis, tachycardia, loss of libido, and elevated hepatic enzyme activities; however, no ophthalmologic toxicity was reported. Although these new adverse reaction signals associated with risdiplam have been defined, long-term clinical studies are needed to confirm these findings. Nevertheless, our findings provide a valuable reference for improving the clinical management of SMA.
2023-04-25 | Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis
To systematically analyze adverse events (AEs) in treatment of spinal muscular atrophy (SMA) with Nusinersen in children and adolescents.The study is registered on PROSPERO (CRD42022345589). Databases were searched and literature relating to Nusinersen in the treatment of spinal muscular atrophy in children from the start of database establishment to December 1, 2022, was retrospectively analyzed. R.3.6.3 statistical software was used, and random effects meta-analysis was performed to calculate weighted mean prevalence and 95% confidence intervals (CI).In total, 15 eligible studies were included, with a total of 967 children. Rate of definite Nusinersen-related AEs was 0.57% (95% CI: 0%-3.97%), and probable Nusinersen-related AEs 7.76% (95% CI: 1.85%-17.22%). Overall rate of AEs was 83.51% (95% CI: 73.55%-93.46%), and serious AEs 33.04% (95% CI: 18.15%-49.91%). For main specific AEs, fever was most common, 40.07% (95% CI: 25.14%-56.02%), followed by upper respiratory tract infection 39.94% (95% CI: 29.43%-50.94%), and pneumonia 26.62% (95% CI: 17.99%-36.25%).The difference in overall AE rates between the two groups (Nusinersen group and placebo group) was significant (OR = 0.27,95% CI: 0.08-0.95, P = 0.042). Moreover, incidence of serious adverse events, and fatal adverse events were both significantly lower than in the placebo group (OR = 0.47, 95%CI: 0.32-0.69, P < 0.01), and (OR = 0.37, 95%CI: 0.23-0.59, P < 0.01), respectively.Nusinersen direct adverse events are rare, and it can effectively reduces common, serious, and fatal adverse events in children and adolescents with spinal muscular atrophy.
2023-01-31 | DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration
Antisense oligonucleotide-mediated (AO-mediated) therapy is a promising strategy to treat several neurological diseases, including spinal muscular atrophy (SMA). However, limited delivery to the CNS with AOs administered intravenously or subcutaneously is a major challenge. Here, we demonstrate a single subcutaneous administration of cell-penetrating peptide DG9 conjugated to an AO called phosphorodiamidate morpholino oligomer (PMO) reached the CNS and significantly prolonged the median survival compared with unconjugated PMO and R6G-PMO in a severe SMA mouse model. Treated mice exhibited substantially higher expression of full-length survival of motor neuron 2 in both the CNS and systemic tissues compared with nontreated and unmodified AO-treated mice. The treatment ameliorated the atrophic musculature and improved breathing function accompanied by improved muscle strength and innervation at the neuromuscular junction with no signs of apparent toxicity. We also demonstrated DG9-conjugated PMO localized in nuclei in the spinal cord and brain after subcutaneous injections. Our data identify DG9 peptide conjugation as a powerful way to improve the efficacy of AO-mediated splice modulation. Finally, DG9-PMO is a promising therapeutic option to treat SMA and other neurological diseases, overcoming the necessity for intrathecal injections and treating body-wide tissues without apparent toxicity.
2021-02-11 | Do we always need to treat patients with spinal muscular atrophy? A personal view and experience
Abstract Background We report the clinical outcomes observed in our patients with SMA type 1 or 2 receiving nusinersen, and we comment on the ethical implications of this treatment, in line with our results and those reported by Audic et al. in their analysis published in the Orphanet Journal of Rare Diseases. Methods We analyzed records of all children with a genetically diagnosed SMA and clinically confirmed diagnosis of SMA Type 1 or 2 to whom nusinersen was offered. Follow-up lasted 30 months. Results Among the 17 children with SMA type 1, 6 interrupted treatment with nusinersen due to adverse events or lack of efficacy. Of the remaining 11 patients, 9 are responding to therapy, though multidisciplinary complex care is still required. All those children started nusinersen at a very early age. Eighteen patients with SMA type 2 received nusinersen; five required treatment interruption. The other 13 patients are still on nusinersen therapy, and 6 are responders. Among the seven non-responders, only two met the inclusion criteria of the pivotal trial. Conclusions Our analysis further supports the findings reported in the study by Audic et al. We believe that a wider use of nusinersen in clinical practice would require a comprehensive assessment of its actual benefits weighed against the discomfort caused to patients, as well as the identification of the patients who may obtain the best benefits from this treatment.
2020-03-27 | Nusinersen as a Therapeutic Agent for Spinal Muscular Atrophy
The reduction of survival motor neuron (SMN) protein causes spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease. Nusinersen is an antisense oligonucleotide, approved by the FDA, which specifically binds to the repressor within SMN2 exon 7 to enhance exon 7 inclusion and augment production of functional SMN protein. Nusinersen is the first new oligonucleotide-based drug targeting the central nervous system for the treatment of SMA. This review of nusinersen will discuss its action mechanism, cellular uptake, trafficking mechanisms, and administration approaches to cross the blood-brain barrier. Furthermore, nusinersen clinical trials will be assessed in terms of pharmacokinetics, tolerability and safety, the clinical outcomes of multiple intrathecal doses, and a discussion on the primary and secondary endpoints.
small molecules
2024-01-05 | Risdiplam in Spinal Muscular Atrophy: Safety Profile and Use Through The Early Access to Medicine Scheme for the Paediatric Cohort in Great Britain
Background: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021. Objective: To describe the largest paediatric European real-world set of data on patients’ characteristics and short-term safety for risdiplam in Great Britain through EAMS. Methods: We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events. Results: Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0–17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients. Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified. Conclusions: This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam’s role in addressing patients’ needs into the future.
2023-10-07 | Safety and Efficacy of Nusinersen and Risdiplam for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Objective: We performed a systematic review and meta-analysis of the efficacy and safety of nusinersen and risdiplam in the treatment of spinal muscular disease (SMA). Methods: We screened the literature published in Pubmed, Web of Science, Embase, and Cochrane before July 2023 to conduct randomized controlled trials to test the treatment of SMA patients with nusinersen and risdiplam. The data were analyzed using Review Manager 5.4 software and Stata version 15.0 software. Results: A total of six randomized controlled trials were included, involving 728 SMA patients, to synthesize evidence. It is reported that nusinersen treatment was beneficial for increasing the score of the Hammersmith Functional Motor Scale—Expanded (HFMSE) (WMD: 4.90; 95% CI: 3.17, 6.63; p < 0.00001), Revised Upper Limb Module (RULM) (WMD: 3.70; 95% CI: 3.30, 4.10; p < 0.00001), and Hammersmith Infant Neurological Evaluation Section 2 (HINE-2) (WMD: 5.21; 95% CI: 4.83, 5.60; p < 0.00001). In addition, the risdiplam treatment group also showed statistically significant improvements in the HFMSE score (WMD:0.87; 95% CI: 0.05, 1.68; p = 0.04), the 32-item Motor Function Measure (MFM32) (WMD:1.48; 95% CI: 0.58, 2.38; p = 0.001), and (WMD: 1.29; 95% CI: 0.57, 2.01; p = 0.0005). Nusinersen and risdiplam did not cause a statistically significant increase in the RULM score for adverse events (OR: 0.93; 95% CI: 0.51, 1.7; p = 0.82) and for severe adverse events (OR: 0.77; 95% CI: 0.47, 1.27; p = 0.31). Conclusion: Our analysis found that nusinersen and risdiplam treatment showed clinically meaningful improvement in motor function and a similar incidence rate of adverse events compared with the placebo. Further research should be carried out to provide a direct comparison between the two drugs in terms of safety and efficacy.
2023-07-12 | Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent
Chronic intermittent hypoxia (CIH)-induced redox alterations underlie diaphragm muscle dysfunction. We sought to establish if NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) underpin CIH-induced changes in diaphragm muscle, which manifest as impaired muscle performance. Adult male mice (C57BL/6J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) administered in the drinking water throughout exposure to CIH. In separate studies, we examined sham and CIH-exposed NOX2-null mice (B6.129S-CybbTM1Din/J). Apocynin co-treatment or NOX2 deletion proved efficacious in entirely preventing diaphragm muscle dysfunction following exposure to CIH. Exposure to CIH had no effect on NOX2 expression. However, NOX4 mRNA expression was increased following exposure to CIH in wild-type and NOX2 null mice. There was no evidence of overt CIH-induced oxidative stress. A NOX2-dependent increase in genes related to muscle regeneration, antioxidant capacity, and autophagy and atrophy was evident following exposure to CIH. We suggest that NOX-dependent CIH-induced diaphragm muscle weakness has the potential to affect ventilatory and non-ventilatory performance of the respiratory system. Therapeutic strategies employing NOX2 blockade may function as an adjunct therapy to improve diaphragm muscle performance and reduce disease burden in diseases characterised by exposure to CIH, such as obstructive sleep apnoea.
2021-11-26 | Mediterranean Diet, Brain and Muscle: Olive Polyphenols and Resveratrol Protection in Neurodegenerative and Neuromuscular Disorders
The Mediterranean diet is worldwide recognized as a good prototype of nutrition due to the conspicuous intake of olive oil, nuts, red wine, legumes, fruit, and vegetables, all fundamental elements rich in antioxidant substances and polyphenols. Polyphenols are a wide range of phytochemicals and/or synthetic chemical compounds with proven beneficial properties for human health. In the present review, we critically summarize the wellcharacterized antioxidant and anti-inflammatory properties of polyphenols contained in the olives and extra virgin olive oil and of resveratrol, a non-flavonoid phenolic compound. We discuss the potential use of these polyphenols as pharmaceutical formulations for the treatment of human diseases. We also show the emerging importance of their consumption in the prevention and management of crucial neurodegenerative conditions (alcohol-related brain disorders and aging) and in neuromuscular disorders (Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy), where oxidative stress plays a predominant role.
2021-07-12 | Risdiplam for the Use of Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is one of the leading causes of death in infants related to the degeneration of neurons. Currently, there are no curative treatment options for SMA, and many options available may not be feasible. This review presents the background, clinical studies, and indications for the use of Risdiplam in treating SMA. SMA causes a decrease in the production of survival motor neuron proteins (SMN) and current treatments target to increase the expression of SMN. Risdiplam is the first and only oral medication to be approved to treat SMA. As an SMN2 splicing modifier, it has provided stronger systemic therapies than previous intrathecal and gene replacement therapies. There have been many efforts to treat SMA with multidisciplinary approaches. These include intrathecal injections to gene replacement therapies. However, these have been faced with limitations such as reaching a good therapeutic dose in systemic tissues, route of administration, and price. Risdiplam is currently the only orally administered drug approved by the FDA for the treatment of SMA. It not only provides a good therapeutic window to systemic tissues but allows for a non-invasive approach in infants. Further investigation and comparison on the safety profile of Risdiplam due to its broader systemic effect should be considered with other available therapies.
gene therapies
2024-05-01 | Deciphering the complexity of IGHMBP2 mutations : respiratory deficits as prognostic indicators of lifespan
According to the National Institutes of Health (NIH), over 10,000 rare diseases have been identified, impacting approximately 1 in 10 individuals, totaling around 30 million people in the United States. Nearly 90 percent of neuromuscular diseases (NMDs) fall under the category of rare diseases. Despite their low prevalence, NMDs are collectively common conditions. NMDs encompass a diverse range of neurological disorders, constituting a significant contributor to mortality and lifelong disability in both children and adults. NMDs include 5q-spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress type 1 (SMARD1), and Charcot Marie Tooth Type 2S (CMT2S). SMA is a motor neuron disease caused by autosomal recessive mutations in the survival motor neuron gene 1 (SMN1) [1]. SMA is one of the most common genetic causes of infant mortality, with an incidence of 1:10,000 [2]. Progressive muscle weakness begins proximally and develops distally with the initial sparing of the diaphragm. As the disease progresses, intercostal muscles become weak, leading to thoracoabdominal asynchrony, a bell-shaped chest, and, eventually, respiratory failure [3]. In contrast, mutations in the immunoglobulin µ-DNA binding protein 2 human gene (IGHMBP2) gene on Chromosome 11q13 give rise to two different autosomal recessive diseases, SMARD1 and CMT2S. The first cases of SMARD1 were described in 1974 [4]. However, these putative SMARD1 cases were thought to be unusual presentations of an unknown etiology causing the most acute type of SMA, Werdnig Hoffman disease (SMA type 1). SMARD1 is a devastating disease: patients present with respiratory distress 1-2 months after birth due to bilateral diaphragmatic weakness and eventration, while xiv progressive distal to proximal muscle defects were not apparent until 3-4 months of age [4]. Conversely, the milder axonal neuropathy, CMT2S, was not described until 2014, after exome sequencing of two English female patients diagnosed previously with CMT2 but with no identified mutation [5]. In this work, we characterize a novel model for CMT2S, Ighmbp2H922Y/H922Y, and the first compound heterozygous model of SMARD1, Ighmbp2D564N/H922Y. Our studies delve into the intricate role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S, revealing significant differences between mouse models with homozygous recessive and compound heterozygous mutations. The H922Y homozygous mice exhibited a normal lifespan and did not display respiratory deficiencies. Mild motor function defects emerged later in life, consistent with CMT2S disease progression. Notably, lifespan cohorts in D564N/H922Y mice exhibited three distinct groups, contrasting with H922Y homozygous mice, which showed no reduction in lifespan. A groundbreaking aspect of the research is the identification of early respiratory pathology as a critical predictor of lifespan within the D564N/H922Y survival cohorts, independent of limb pathology. Moreover, this study uniquely separates IGHMBP2 function in respiration from limb motor function, underscoring the significant improvement in lifespan and fitness by reducing respiratory deficits. The findings establish a direct correlation between IGHMBP2 biochemical activity and disease pathogenesis associated with patient mutations in humans and mice, advancing our understanding of IGHMBP2 function and its impact on disease progression.
2024-03-19 | Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System
The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively.
2024-03-14 | Respiratory morbidity in patients with spinal muscular atrophy—a changing world in the light of disease-modifying therapies
Respiratory complications are common in spinal muscular atrophy (SMA) and significantly contribute to morbidity and mortality in these patients. Generalized respiratory and bulbar muscle weakness translates into diverse and complex clinical consequences necessitating strict follow-up and specialized care. The natural history of SMA has evolved drastically in recent years as a result of the introduction of novel, disease-modifying therapies. While the impact of these therapies on motor function is well described in literature, its consequence for respiratory management has not been extensively studied. In this review we aim to provide a comprehensive overview of the respiratory morbidities, their follow-up, management, and the impact of novel therapies in SMA.
2023-12-13 | Adeno-associated viruses in gene therapy for spinal muscular atrophies: trend or triumph?
The development of gene therapy in the 21st century is largely based on application of viral vectors, which have shown their effectiveness along with a fairly high safety profile. Among the vector systems, one of the leading places was taken by adeno-associated viruses (AAV), on the basis of which drugs were created for the treatment of severe hereditary monogenic diseases, including spinal muscular atrophies (SMA). Their use, on the one hand, is justified by the flexibility of AAV as a platform for the creation of gene therapy drugs, and on the other hand, it is often perceived as a kind of trend that has significant limitations. In this review, the focus is on two main aspects: AAV as a vector for the treatment of diseases from the SMA group and possible directions of development in this area and in gene therapy in general.
The review operates with recent data published after clinical trials and experimental studies during last decade, and also critically examines the possibilities of gene therapy using AAV, mentioning other existing approaches, incl. medical therapy for SMA.
Attention is also paid to the situation in the field of using AAV for the treatment of other hereditary diseases and the most acute problems faced by the use of drugs created on the basis of this promising vector system.
2023-06-16 | In Vitro Modeling as a Tool for Testing Therapeutics for Spinal Muscular Atrophy and IGHMBP2-Related Disorders
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infant mortality. The most common form of SMA is caused by mutations in the SMN1 gene, located on 5q (SMA). On the other hand, mutations in IGHMBP2 lead to a large disease spectrum with no clear genotype-phenotype correlation, which includes Spinal Muscular Atrophy with Muscular Distress type 1 (SMARD1), an extremely rare form of SMA, and Charcot-Marie-Tooth 2S (CMT2S). We optimized a patient-derived in vitro model system that allows us to expand research on disease pathogenesis and gene function, as well as test the response to the AAV gene therapies we have translated to the clinic. We generated and characterized induced neurons (iN) from SMA and SMARD1/CMT2S patient cell lines. After establishing the lines, we treated the generated neurons with AAV9-mediated gene therapy (AAV9.SMN (Zolgensma) for SMA and AAV9.IGHMBP2 for IGHMBP2 disorders (NCT05152823)) to evaluate the response to treatment. The iNs of both diseases show a characteristic short neurite length and defects in neuronal conversion, which have been reported in the literature before with iPSC modeling. SMA iNs respond to treatment with AAV9.SMN in vitro, showing a partial rescue of the morphology phenotype. For SMARD1/CMT2S iNs, we were able to observe an improvement in the neurite length of neurons after the restoration of IGHMBP2 in all disease cell lines, albeit to a variable extent, with some lines showing better responses to treatment than others. Moreover, this protocol allowed us to classify a variant of uncertain significance on IGHMBP2 on a suspected SMARD1/CMT2S patient. This study will further the understanding of SMA, and SMARD1/CMT2S disease in particular, in the context of variable patient mutations, and might further the development of new treatments, which are urgently needed.
cell therapies
2022-08-18 | Inspiratory Muscle Rehabilitation Training in Pediatrics: What Is the Evidence?
Pulmonary rehabilitation is typically used for reducing respiratory symptoms and improving fitness and quality of life for patients with chronic lung disease. However, it is rarely prescribed and may be underused in pediatric conditions. Pulmonary rehabilitation can include inspiratory muscle training that improves the strength and endurance of the respiratory muscles. The purpose of this narrative review is to summarize the current literature related to inspiratory muscle rehabilitation training (IMRT) in healthy and diseased pediatric populations. This review highlights the different methods of IMRT and their effects on respiratory musculature in children. Available literature demonstrates that IMRT can improve respiratory muscle strength and endurance, perceived dyspnea and exertion, maximum voluntary ventilation, and exercise performance in the pediatric population. These mechanistic changes help explain improvements in symptomology and clinical outcomes with IMRT and highlight our evolving understanding of the role of IMRT in pediatric patients. There remains considerable heterogeneity in the literature related to the type of training utilized, training protocols, duration of the training, use of control versus placebo, and reported outcome measures. There is a need to test and refine different IMRT protocols, conduct larger randomized controlled trials, and include patient-centered clinical outcomes to help improve the evidence base and support the use of IMRT in patient care.
2018-08-17 | Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy
Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders.
2017-01-07 | Cellular Therapy for Spinal Muscular Atrophy
Spinal muscular atrophies (SMAs) include a series of neuromuscular genetic disorders due to mutations in the survival motor neuron 1 (SMN1) gene. The SMA 5q form represents the most common genetic cause of death during childhood affecting about 1 in 10,000 newborns. There is currently no effective therapy for these patients other than supportive care, even though remarkable progress has been observed during the last decade in the development of molecular and gene therapies. However, SMN-augmentation strategies would not be completely efficacious in already symptomatic patients. Additional therapeutic approaches include stem cell transplantation, which could be exploited to enhance the neuromuscular repair system through both cell replacement and environmental support. In this chapter, we examine the cell-based therapeutic strategies that are currently under development for the treatment of SMAs, discussing state-of-the-art research and challenges toward a safe and effective cure for the disease.
2016-10-28 | Addressing Cell Therapy for Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a devastating neuromuscular disease that affects children and young adults. The degeneration of spinal motor neurons, which are primarily involved in this disease, results in progressive muscular weakness and atrophy. As of 2016, there is no effective clinical treatment available for SMA patients, even if a large number of therapeutic approaches are being tested worldwide. Stem cells have been considered as a potential therapeutic strategy due to their plasticity and ability to direct differentiation in response to extracellular signals. Current cell-based therapies employ multiple types of stem cells to modify disease pathophysiology. This is theoretically achieved by either supporting neurons and glial cells through the release of neurotrophic factors, or directly replacing them. This chapter focuses on the therapeutic potential of different subtypes of human pluripotent stem cells and their derived phenotypes for SMA. This chapter also briefly describes their contribution in disease pathogenesis understanding. Finally, the chapter discusses the main challenges to overcome for stem cell therapeutic clinical translation.
2015-09-01 | Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury
Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express the major glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in spinal cord. Following SCI, compromised GLT1 expression/function can increase susceptibility to excitotoxicity. We therefore evaluated intraspinal transplantation of human iPS cell-derived astrocytes (hIPSAs) following cervical contusion SCI as a novel strategy for reconstituting GLT1 expression and for protecting diaphragmatic respiratory neural circuitry. Transplant-derived cells showed robust long-term survival post-injection and efficiently differentiated into astrocytes in injured spinal cord of both immunesuppressed mice and rats. However, the majority of transplant-derived astrocytes did not express high levels of GLT1, particularly at early times post-injection. To enhance their ability to modulate extracellular glutamate levels, we engineered hIPSAs with lentivirus to constitutively express GLT1. Overexpression significantly increased GLT1 protein and functional GLT1-mediated glutamate uptake levels in hIPSAs both in vitro and in vivo post-transplantation. Compared to human fibroblast control and unmodified hIPSA transplantation, GLT1-overexpressing hIPSAs reduced (1) lesion size within the injured cervical spinal cord, (2) morphological denervation by respiratory phrenic motor neurons at the diaphragm neuromuscular junction, and (3) functional diaphragm denervation as measured by recording of spontaneous EMGs and evoked compound muscle action potentials. Our findings demonstrate that hiPSA transplantation is a therapeutically-powerful approach for SCI.
oligonucleotides
2024-03-01 | Exploration of adverse events associated with risdiplam use: Retrospective cases from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database
Risdiplam is a new drug for treating spinal muscular atrophy (SMA). However, pharmacovigilance analyses are necessary to objectively evaluate its safety—a crucial step in preventing severe adverse events (AEs). Accordingly, the primary objective of the current study was to examine the AEs associated with risdiplam use based on real-world data obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. More specifically, we examined incidents reported between the third quarter of 2020 and the second quarter of 2023. The imbalance of risdiplam-related AEs was evaluated by computing the reporting odds ratio. A total of 5,406,334 reports were thoroughly reviewed. By removing duplicate reports, we identified 1588 reports in which risdiplam was the main suspected drug whose use was accompanied by 3470 associated AEs. Among the included AEs, 703 were categorized as serious and 885 as non-serious. Risdiplam use induced AEs across 18 organ systems, resulting in 130 positive signals. Notably, we detected new AE signals, including cardiac arrest, nephrolithiasis, tachycardia, loss of libido, and elevated hepatic enzyme activities; however, no ophthalmologic toxicity was reported. Although these new adverse reaction signals associated with risdiplam have been defined, long-term clinical studies are needed to confirm these findings. Nevertheless, our findings provide a valuable reference for improving the clinical management of SMA.
2023-04-25 | Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis
To systematically analyze adverse events (AEs) in treatment of spinal muscular atrophy (SMA) with Nusinersen in children and adolescents.The study is registered on PROSPERO (CRD42022345589). Databases were searched and literature relating to Nusinersen in the treatment of spinal muscular atrophy in children from the start of database establishment to December 1, 2022, was retrospectively analyzed. R.3.6.3 statistical software was used, and random effects meta-analysis was performed to calculate weighted mean prevalence and 95% confidence intervals (CI).In total, 15 eligible studies were included, with a total of 967 children. Rate of definite Nusinersen-related AEs was 0.57% (95% CI: 0%-3.97%), and probable Nusinersen-related AEs 7.76% (95% CI: 1.85%-17.22%). Overall rate of AEs was 83.51% (95% CI: 73.55%-93.46%), and serious AEs 33.04% (95% CI: 18.15%-49.91%). For main specific AEs, fever was most common, 40.07% (95% CI: 25.14%-56.02%), followed by upper respiratory tract infection 39.94% (95% CI: 29.43%-50.94%), and pneumonia 26.62% (95% CI: 17.99%-36.25%).The difference in overall AE rates between the two groups (Nusinersen group and placebo group) was significant (OR = 0.27,95% CI: 0.08-0.95, P = 0.042). Moreover, incidence of serious adverse events, and fatal adverse events were both significantly lower than in the placebo group (OR = 0.47, 95%CI: 0.32-0.69, P < 0.01), and (OR = 0.37, 95%CI: 0.23-0.59, P < 0.01), respectively.Nusinersen direct adverse events are rare, and it can effectively reduces common, serious, and fatal adverse events in children and adolescents with spinal muscular atrophy.
2023-01-31 | DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration
Antisense oligonucleotide-mediated (AO-mediated) therapy is a promising strategy to treat several neurological diseases, including spinal muscular atrophy (SMA). However, limited delivery to the CNS with AOs administered intravenously or subcutaneously is a major challenge. Here, we demonstrate a single subcutaneous administration of cell-penetrating peptide DG9 conjugated to an AO called phosphorodiamidate morpholino oligomer (PMO) reached the CNS and significantly prolonged the median survival compared with unconjugated PMO and R6G-PMO in a severe SMA mouse model. Treated mice exhibited substantially higher expression of full-length survival of motor neuron 2 in both the CNS and systemic tissues compared with nontreated and unmodified AO-treated mice. The treatment ameliorated the atrophic musculature and improved breathing function accompanied by improved muscle strength and innervation at the neuromuscular junction with no signs of apparent toxicity. We also demonstrated DG9-conjugated PMO localized in nuclei in the spinal cord and brain after subcutaneous injections. Our data identify DG9 peptide conjugation as a powerful way to improve the efficacy of AO-mediated splice modulation. Finally, DG9-PMO is a promising therapeutic option to treat SMA and other neurological diseases, overcoming the necessity for intrathecal injections and treating body-wide tissues without apparent toxicity.
2021-02-11 | Do we always need to treat patients with spinal muscular atrophy? A personal view and experience
Abstract Background We report the clinical outcomes observed in our patients with SMA type 1 or 2 receiving nusinersen, and we comment on the ethical implications of this treatment, in line with our results and those reported by Audic et al. in their analysis published in the Orphanet Journal of Rare Diseases. Methods We analyzed records of all children with a genetically diagnosed SMA and clinically confirmed diagnosis of SMA Type 1 or 2 to whom nusinersen was offered. Follow-up lasted 30 months. Results Among the 17 children with SMA type 1, 6 interrupted treatment with nusinersen due to adverse events or lack of efficacy. Of the remaining 11 patients, 9 are responding to therapy, though multidisciplinary complex care is still required. All those children started nusinersen at a very early age. Eighteen patients with SMA type 2 received nusinersen; five required treatment interruption. The other 13 patients are still on nusinersen therapy, and 6 are responders. Among the seven non-responders, only two met the inclusion criteria of the pivotal trial. Conclusions Our analysis further supports the findings reported in the study by Audic et al. We believe that a wider use of nusinersen in clinical practice would require a comprehensive assessment of its actual benefits weighed against the discomfort caused to patients, as well as the identification of the patients who may obtain the best benefits from this treatment.
2020-03-27 | Nusinersen as a Therapeutic Agent for Spinal Muscular Atrophy
The reduction of survival motor neuron (SMN) protein causes spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease. Nusinersen is an antisense oligonucleotide, approved by the FDA, which specifically binds to the repressor within SMN2 exon 7 to enhance exon 7 inclusion and augment production of functional SMN protein. Nusinersen is the first new oligonucleotide-based drug targeting the central nervous system for the treatment of SMA. This review of nusinersen will discuss its action mechanism, cellular uptake, trafficking mechanisms, and administration approaches to cross the blood-brain barrier. Furthermore, nusinersen clinical trials will be assessed in terms of pharmacokinetics, tolerability and safety, the clinical outcomes of multiple intrathecal doses, and a discussion on the primary and secondary endpoints.
small molecules
2024-01-05 | Risdiplam in Spinal Muscular Atrophy: Safety Profile and Use Through The Early Access to Medicine Scheme for the Paediatric Cohort in Great Britain
Background: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021. Objective: To describe the largest paediatric European real-world set of data on patients’ characteristics and short-term safety for risdiplam in Great Britain through EAMS. Methods: We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events. Results: Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0–17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients. Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified. Conclusions: This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam’s role in addressing patients’ needs into the future.
2023-10-07 | Safety and Efficacy of Nusinersen and Risdiplam for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Objective: We performed a systematic review and meta-analysis of the efficacy and safety of nusinersen and risdiplam in the treatment of spinal muscular disease (SMA). Methods: We screened the literature published in Pubmed, Web of Science, Embase, and Cochrane before July 2023 to conduct randomized controlled trials to test the treatment of SMA patients with nusinersen and risdiplam. The data were analyzed using Review Manager 5.4 software and Stata version 15.0 software. Results: A total of six randomized controlled trials were included, involving 728 SMA patients, to synthesize evidence. It is reported that nusinersen treatment was beneficial for increasing the score of the Hammersmith Functional Motor Scale—Expanded (HFMSE) (WMD: 4.90; 95% CI: 3.17, 6.63; p < 0.00001), Revised Upper Limb Module (RULM) (WMD: 3.70; 95% CI: 3.30, 4.10; p < 0.00001), and Hammersmith Infant Neurological Evaluation Section 2 (HINE-2) (WMD: 5.21; 95% CI: 4.83, 5.60; p < 0.00001). In addition, the risdiplam treatment group also showed statistically significant improvements in the HFMSE score (WMD:0.87; 95% CI: 0.05, 1.68; p = 0.04), the 32-item Motor Function Measure (MFM32) (WMD:1.48; 95% CI: 0.58, 2.38; p = 0.001), and (WMD: 1.29; 95% CI: 0.57, 2.01; p = 0.0005). Nusinersen and risdiplam did not cause a statistically significant increase in the RULM score for adverse events (OR: 0.93; 95% CI: 0.51, 1.7; p = 0.82) and for severe adverse events (OR: 0.77; 95% CI: 0.47, 1.27; p = 0.31). Conclusion: Our analysis found that nusinersen and risdiplam treatment showed clinically meaningful improvement in motor function and a similar incidence rate of adverse events compared with the placebo. Further research should be carried out to provide a direct comparison between the two drugs in terms of safety and efficacy.
2023-07-12 | Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent
Chronic intermittent hypoxia (CIH)-induced redox alterations underlie diaphragm muscle dysfunction. We sought to establish if NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) underpin CIH-induced changes in diaphragm muscle, which manifest as impaired muscle performance. Adult male mice (C57BL/6J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) administered in the drinking water throughout exposure to CIH. In separate studies, we examined sham and CIH-exposed NOX2-null mice (B6.129S-CybbTM1Din/J). Apocynin co-treatment or NOX2 deletion proved efficacious in entirely preventing diaphragm muscle dysfunction following exposure to CIH. Exposure to CIH had no effect on NOX2 expression. However, NOX4 mRNA expression was increased following exposure to CIH in wild-type and NOX2 null mice. There was no evidence of overt CIH-induced oxidative stress. A NOX2-dependent increase in genes related to muscle regeneration, antioxidant capacity, and autophagy and atrophy was evident following exposure to CIH. We suggest that NOX-dependent CIH-induced diaphragm muscle weakness has the potential to affect ventilatory and non-ventilatory performance of the respiratory system. Therapeutic strategies employing NOX2 blockade may function as an adjunct therapy to improve diaphragm muscle performance and reduce disease burden in diseases characterised by exposure to CIH, such as obstructive sleep apnoea.
2021-11-26 | Mediterranean Diet, Brain and Muscle: Olive Polyphenols and Resveratrol Protection in Neurodegenerative and Neuromuscular Disorders
The Mediterranean diet is worldwide recognized as a good prototype of nutrition due to the conspicuous intake of olive oil, nuts, red wine, legumes, fruit, and vegetables, all fundamental elements rich in antioxidant substances and polyphenols. Polyphenols are a wide range of phytochemicals and/or synthetic chemical compounds with proven beneficial properties for human health. In the present review, we critically summarize the wellcharacterized antioxidant and anti-inflammatory properties of polyphenols contained in the olives and extra virgin olive oil and of resveratrol, a non-flavonoid phenolic compound. We discuss the potential use of these polyphenols as pharmaceutical formulations for the treatment of human diseases. We also show the emerging importance of their consumption in the prevention and management of crucial neurodegenerative conditions (alcohol-related brain disorders and aging) and in neuromuscular disorders (Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy), where oxidative stress plays a predominant role.
2021-07-12 | Risdiplam for the Use of Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is one of the leading causes of death in infants related to the degeneration of neurons. Currently, there are no curative treatment options for SMA, and many options available may not be feasible. This review presents the background, clinical studies, and indications for the use of Risdiplam in treating SMA. SMA causes a decrease in the production of survival motor neuron proteins (SMN) and current treatments target to increase the expression of SMN. Risdiplam is the first and only oral medication to be approved to treat SMA. As an SMN2 splicing modifier, it has provided stronger systemic therapies than previous intrathecal and gene replacement therapies. There have been many efforts to treat SMA with multidisciplinary approaches. These include intrathecal injections to gene replacement therapies. However, these have been faced with limitations such as reaching a good therapeutic dose in systemic tissues, route of administration, and price. Risdiplam is currently the only orally administered drug approved by the FDA for the treatment of SMA. It not only provides a good therapeutic window to systemic tissues but allows for a non-invasive approach in infants. Further investigation and comparison on the safety profile of Risdiplam due to its broader systemic effect should be considered with other available therapies.
gene therapies
2024-05-01 | Deciphering the complexity of IGHMBP2 mutations : respiratory deficits as prognostic indicators of lifespan
According to the National Institutes of Health (NIH), over 10,000 rare diseases have been identified, impacting approximately 1 in 10 individuals, totaling around 30 million people in the United States. Nearly 90 percent of neuromuscular diseases (NMDs) fall under the category of rare diseases. Despite their low prevalence, NMDs are collectively common conditions. NMDs encompass a diverse range of neurological disorders, constituting a significant contributor to mortality and lifelong disability in both children and adults. NMDs include 5q-spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress type 1 (SMARD1), and Charcot Marie Tooth Type 2S (CMT2S). SMA is a motor neuron disease caused by autosomal recessive mutations in the survival motor neuron gene 1 (SMN1) [1]. SMA is one of the most common genetic causes of infant mortality, with an incidence of 1:10,000 [2]. Progressive muscle weakness begins proximally and develops distally with the initial sparing of the diaphragm. As the disease progresses, intercostal muscles become weak, leading to thoracoabdominal asynchrony, a bell-shaped chest, and, eventually, respiratory failure [3]. In contrast, mutations in the immunoglobulin µ-DNA binding protein 2 human gene (IGHMBP2) gene on Chromosome 11q13 give rise to two different autosomal recessive diseases, SMARD1 and CMT2S. The first cases of SMARD1 were described in 1974 [4]. However, these putative SMARD1 cases were thought to be unusual presentations of an unknown etiology causing the most acute type of SMA, Werdnig Hoffman disease (SMA type 1). SMARD1 is a devastating disease: patients present with respiratory distress 1-2 months after birth due to bilateral diaphragmatic weakness and eventration, while xiv progressive distal to proximal muscle defects were not apparent until 3-4 months of age [4]. Conversely, the milder axonal neuropathy, CMT2S, was not described until 2014, after exome sequencing of two English female patients diagnosed previously with CMT2 but with no identified mutation [5]. In this work, we characterize a novel model for CMT2S, Ighmbp2H922Y/H922Y, and the first compound heterozygous model of SMARD1, Ighmbp2D564N/H922Y. Our studies delve into the intricate role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S, revealing significant differences between mouse models with homozygous recessive and compound heterozygous mutations. The H922Y homozygous mice exhibited a normal lifespan and did not display respiratory deficiencies. Mild motor function defects emerged later in life, consistent with CMT2S disease progression. Notably, lifespan cohorts in D564N/H922Y mice exhibited three distinct groups, contrasting with H922Y homozygous mice, which showed no reduction in lifespan. A groundbreaking aspect of the research is the identification of early respiratory pathology as a critical predictor of lifespan within the D564N/H922Y survival cohorts, independent of limb pathology. Moreover, this study uniquely separates IGHMBP2 function in respiration from limb motor function, underscoring the significant improvement in lifespan and fitness by reducing respiratory deficits. The findings establish a direct correlation between IGHMBP2 biochemical activity and disease pathogenesis associated with patient mutations in humans and mice, advancing our understanding of IGHMBP2 function and its impact on disease progression.
2024-03-19 | Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System
The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively.
2024-03-14 | Respiratory morbidity in patients with spinal muscular atrophy—a changing world in the light of disease-modifying therapies
Respiratory complications are common in spinal muscular atrophy (SMA) and significantly contribute to morbidity and mortality in these patients. Generalized respiratory and bulbar muscle weakness translates into diverse and complex clinical consequences necessitating strict follow-up and specialized care. The natural history of SMA has evolved drastically in recent years as a result of the introduction of novel, disease-modifying therapies. While the impact of these therapies on motor function is well described in literature, its consequence for respiratory management has not been extensively studied. In this review we aim to provide a comprehensive overview of the respiratory morbidities, their follow-up, management, and the impact of novel therapies in SMA.
2023-12-13 | Adeno-associated viruses in gene therapy for spinal muscular atrophies: trend or triumph?
The development of gene therapy in the 21st century is largely based on application of viral vectors, which have shown their effectiveness along with a fairly high safety profile. Among the vector systems, one of the leading places was taken by adeno-associated viruses (AAV), on the basis of which drugs were created for the treatment of severe hereditary monogenic diseases, including spinal muscular atrophies (SMA). Their use, on the one hand, is justified by the flexibility of AAV as a platform for the creation of gene therapy drugs, and on the other hand, it is often perceived as a kind of trend that has significant limitations. In this review, the focus is on two main aspects: AAV as a vector for the treatment of diseases from the SMA group and possible directions of development in this area and in gene therapy in general.
The review operates with recent data published after clinical trials and experimental studies during last decade, and also critically examines the possibilities of gene therapy using AAV, mentioning other existing approaches, incl. medical therapy for SMA.
Attention is also paid to the situation in the field of using AAV for the treatment of other hereditary diseases and the most acute problems faced by the use of drugs created on the basis of this promising vector system.
2023-06-16 | In Vitro Modeling as a Tool for Testing Therapeutics for Spinal Muscular Atrophy and IGHMBP2-Related Disorders
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infant mortality. The most common form of SMA is caused by mutations in the SMN1 gene, located on 5q (SMA). On the other hand, mutations in IGHMBP2 lead to a large disease spectrum with no clear genotype-phenotype correlation, which includes Spinal Muscular Atrophy with Muscular Distress type 1 (SMARD1), an extremely rare form of SMA, and Charcot-Marie-Tooth 2S (CMT2S). We optimized a patient-derived in vitro model system that allows us to expand research on disease pathogenesis and gene function, as well as test the response to the AAV gene therapies we have translated to the clinic. We generated and characterized induced neurons (iN) from SMA and SMARD1/CMT2S patient cell lines. After establishing the lines, we treated the generated neurons with AAV9-mediated gene therapy (AAV9.SMN (Zolgensma) for SMA and AAV9.IGHMBP2 for IGHMBP2 disorders (NCT05152823)) to evaluate the response to treatment. The iNs of both diseases show a characteristic short neurite length and defects in neuronal conversion, which have been reported in the literature before with iPSC modeling. SMA iNs respond to treatment with AAV9.SMN in vitro, showing a partial rescue of the morphology phenotype. For SMARD1/CMT2S iNs, we were able to observe an improvement in the neurite length of neurons after the restoration of IGHMBP2 in all disease cell lines, albeit to a variable extent, with some lines showing better responses to treatment than others. Moreover, this protocol allowed us to classify a variant of uncertain significance on IGHMBP2 on a suspected SMARD1/CMT2S patient. This study will further the understanding of SMA, and SMARD1/CMT2S disease in particular, in the context of variable patient mutations, and might further the development of new treatments, which are urgently needed.
cell therapies
2022-08-18 | Inspiratory Muscle Rehabilitation Training in Pediatrics: What Is the Evidence?
Pulmonary rehabilitation is typically used for reducing respiratory symptoms and improving fitness and quality of life for patients with chronic lung disease. However, it is rarely prescribed and may be underused in pediatric conditions. Pulmonary rehabilitation can include inspiratory muscle training that improves the strength and endurance of the respiratory muscles. The purpose of this narrative review is to summarize the current literature related to inspiratory muscle rehabilitation training (IMRT) in healthy and diseased pediatric populations. This review highlights the different methods of IMRT and their effects on respiratory musculature in children. Available literature demonstrates that IMRT can improve respiratory muscle strength and endurance, perceived dyspnea and exertion, maximum voluntary ventilation, and exercise performance in the pediatric population. These mechanistic changes help explain improvements in symptomology and clinical outcomes with IMRT and highlight our evolving understanding of the role of IMRT in pediatric patients. There remains considerable heterogeneity in the literature related to the type of training utilized, training protocols, duration of the training, use of control versus placebo, and reported outcome measures. There is a need to test and refine different IMRT protocols, conduct larger randomized controlled trials, and include patient-centered clinical outcomes to help improve the evidence base and support the use of IMRT in patient care.
2018-08-17 | Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy
Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders.
2017-01-07 | Cellular Therapy for Spinal Muscular Atrophy
Spinal muscular atrophies (SMAs) include a series of neuromuscular genetic disorders due to mutations in the survival motor neuron 1 (SMN1) gene. The SMA 5q form represents the most common genetic cause of death during childhood affecting about 1 in 10,000 newborns. There is currently no effective therapy for these patients other than supportive care, even though remarkable progress has been observed during the last decade in the development of molecular and gene therapies. However, SMN-augmentation strategies would not be completely efficacious in already symptomatic patients. Additional therapeutic approaches include stem cell transplantation, which could be exploited to enhance the neuromuscular repair system through both cell replacement and environmental support. In this chapter, we examine the cell-based therapeutic strategies that are currently under development for the treatment of SMAs, discussing state-of-the-art research and challenges toward a safe and effective cure for the disease.
2016-10-28 | Addressing Cell Therapy for Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a devastating neuromuscular disease that affects children and young adults. The degeneration of spinal motor neurons, which are primarily involved in this disease, results in progressive muscular weakness and atrophy. As of 2016, there is no effective clinical treatment available for SMA patients, even if a large number of therapeutic approaches are being tested worldwide. Stem cells have been considered as a potential therapeutic strategy due to their plasticity and ability to direct differentiation in response to extracellular signals. Current cell-based therapies employ multiple types of stem cells to modify disease pathophysiology. This is theoretically achieved by either supporting neurons and glial cells through the release of neurotrophic factors, or directly replacing them. This chapter focuses on the therapeutic potential of different subtypes of human pluripotent stem cells and their derived phenotypes for SMA. This chapter also briefly describes their contribution in disease pathogenesis understanding. Finally, the chapter discusses the main challenges to overcome for stem cell therapeutic clinical translation.
2015-09-01 | Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury
Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express the major glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in spinal cord. Following SCI, compromised GLT1 expression/function can increase susceptibility to excitotoxicity. We therefore evaluated intraspinal transplantation of human iPS cell-derived astrocytes (hIPSAs) following cervical contusion SCI as a novel strategy for reconstituting GLT1 expression and for protecting diaphragmatic respiratory neural circuitry. Transplant-derived cells showed robust long-term survival post-injection and efficiently differentiated into astrocytes in injured spinal cord of both immunesuppressed mice and rats. However, the majority of transplant-derived astrocytes did not express high levels of GLT1, particularly at early times post-injection. To enhance their ability to modulate extracellular glutamate levels, we engineered hIPSAs with lentivirus to constitutively express GLT1. Overexpression significantly increased GLT1 protein and functional GLT1-mediated glutamate uptake levels in hIPSAs both in vitro and in vivo post-transplantation. Compared to human fibroblast control and unmodified hIPSA transplantation, GLT1-overexpressing hIPSAs reduced (1) lesion size within the injured cervical spinal cord, (2) morphological denervation by respiratory phrenic motor neurons at the diaphragm neuromuscular junction, and (3) functional diaphragm denervation as measured by recording of spontaneous EMGs and evoked compound muscle action potentials. Our findings demonstrate that hiPSA transplantation is a therapeutically-powerful approach for SCI.
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