Current evidence for treatment with nusinersen for spinal muscular atrophy : a systematic review

Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options currently exist for this autosomal recessive motor neuron disorder. Nusinersen is developed for intrathecal use and binds to a specific sequence within the survival motor neuron 2 pre-messenger RNA, modifying the splicing process to promote expression of full-length survival motor neuron protein. We performed a MEDLINE and CENTRAL search to investigate the current evidence for treatment with nusinersen in patients with spinal muscular atrophy. Four papers were withheld, including two phase-3 randomized controlled trials, one phase-2 open-label clinical trial and one phase-1 open-label clinical trial. Outcome measures concerned improvement in motor function and milestones, as well as event-free survival and survival. Results of these trials are hopeful with significant and clinically meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy, although this does not restore age-appropriate function. Intrathecal nusinersen has acceptable safety and tolerability. Further trials regarding long-term effects and safety aspects as well as trials including broader spinal muscular atrophy and age categories are required and ongoing

The Relationship between Body Composition, Fatty Acid Metabolism and Diet in Spinal Muscular Atrophy

Acknowledgments: I.B. received a studentship from SMA Angels Charity. M.B.’s SMA research isfunded by SMA Angels Charity, Muscular Dystrophy UK, Action Medical Research and SMA UK. S.H.P.’s SMA research is funded by SMA Europe and Anatomical Society.Peer reviewedPublisher PD

Clinical Trial Readiness for Spinal Muscular Atrophy: Experience of an International Educational-Training Initiative

Several successful clinical trials have been conducted in spinal muscular atrophy (SMA) over recent years which have led to the approval of splicing modifiers and gene transfer therapies. With an increasing number of other agents progressing through pre-clinical and clinical development, increasing worldwide clinical trial readiness is becoming essential.SMA Europe initiated a clinical trial readiness project, which included the development of a pilot face-to-face educational-training initiative for clinical specialists and physiotherapists involved in SMA, with an emphasis on the patient perspective. Participants were selected through two surveys and, ahead of the meeting, a mock protocol with specific questions was provided. The initiative involved a series of presentations, role-play and interactive exercises. We describe here our experience and evaluation of this educational-training initiative, emphasising scientific aspects, psychosocial implications and level of satisfaction.From a participant, patient and industry perspective, such training was considered successful and met the objective, which was to improve clinical trial readiness in emerging sites. Resource planning, ethical considerations and communication with patients were identified as three important topics for future training. This initiative highlights the need to develop a training programme to achieve clinical trial readiness across Europe and showcases a collaborative effort with different stakeholders, clinicians, patient advocacy groups and sponsors to address an important issue

The Rise of RNA-Based Therapeutics: Recent Advances and Therapeutic Potential

In recent years, RNA-based therapeutics have emerged as a groundbreaking field, offering innovative approaches for drug development and therapeutic interventions. This review article presents a comprehensive exploration of the advancements in RNA-based therapeutics, focusing on key modalities such as RNA interference (RNAi), antisense oligonucleotides (ASOs), messenger RNA (mRNA) vaccines, and other emerging RNA-based therapies. The introduction provides an insightful overview of the potential of RNA as a therapeutic target, highlighting its unique mechanisms of action and its transformative role in precision medicine. Subsequently, the review delves into the intricacies of RNAi, explaining the function of small interfering RNAs (siRNAs) and microRNAs (miRNAs) in selectively silencing disease-associated genes, thereby opening new avenues for therapeutic interventions. Antisense oligonucleotides (ASOs) are discussed in detail, elucidating how they target mRNA for degradation or modulation of splicing, offering promising solutions for treating genetic disorders, neurodegenerative diseases, and viral infections. Additionally, the groundbreaking success of mRNA vaccines is explored, with an emphasis on their role in combatting infectious diseases like COVID-19 and their potential application in cancer immunotherapy and other therapeutic areas. Addressing the critical issue of delivery challenges in RNA-based therapeutics, the review presents various strategies to enhance stability, cellular uptake, and minimize immunogenicity, thereby improving the effectiveness of these therapies in reaching their intended targets. Clinical successes and challenges of RNA-based therapeutics are critically evaluated, providing insights into ongoing clinical trials and approved therapies. Success stories underscore the transformative potential of RNA-based treatments, while safety concerns are addressed, paving the way for safer and more efficient therapeutic applications. The review concludes by exploring future prospects and innovations in the field, highlighting novel delivery strategies, advancements in RNA editing technologies, and the promise of combination therapies to augment therapeutic outcomes. Regulatory considerations and commercialization challenges are also discussed, offering an understanding of the regulatory landscape for RNA-based therapeutics and the potential for market growth. In conclusion, this review article serves as an informative resource for researchers, clinicians, and pharmaceutical professionals, shedding light on the rapid progress in RNA-based therapeutics and their potential to revolutionize disease treatment. By integrating knowledge from diverse sources, this review contributes to advancing the field and underscores the exciting possibilities of RNA-based interventions in improving patient outcomes and addressing unmet medical needs

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients