Introduction: The clinical application of disease modifying therapies has dramatically changed the paradigm of the management of people with spinal muscular atrophy (SMA), from sole reliance on symptomatic care directed toward the downstream consequences of muscle weakness, to proactive intervention and even preventative care.
Areas covered: In this perspective, the authors evaluate the contemporary therapeutic landscape of SMA and discuss the evolution of novel phenotypes and the treatment algorithm, including the key factors that define individual treatment choice and treatment response. The benefits achieved by early diagnosis and treatment through newborn screening are highlighted, alongside an appraisal of emerging prognostic methods and classification frameworks to inform clinicians, patients, and families about disease course, manage expectations, and improve care planning. A future perspective of unmet needs and challenges is provided, emphasizing the key role of research.
Expert opinion: SMN-augmenting therapies have improved health outcomes for people with SMA and powered the practice of personalized medicine. Within this new proactive diagnostic and treatment paradigm, new phenotypes and different disease trajectories are emerging. Ongoing collaborative research efforts to understand the biology of SMA and define optimal response are critical to refining future approaches.
Keywords: RNA therapy; Spinal Muscular Atrophy; disease modifying therapies; gene therapy; newborn screening; phenotypes.
The outlook for individuals with Spinal Muscular Atrophy (SMA) has transformed with the approval of three effective disease modifying therapies in the past seven years. This group of genetic diseases that cause progressive muscle weakness and present as a broad range of severity – from mild disease with near normal lifespan to severe with abbreviated lifespan and comorbidities – now have gene-based therapies that have shown (motor) functional gains, ameliorated comorbidities, and improved overall quality of life of patients and prolonged survival. With the rapid translation of early diagnostic paradigms through newborn screening and the acceleration of a therapeutic pipeline, uncertainties within clinical practice arise including the optimal time to treat, the changing clinical characteristics of the treated population, monitoring of disease progression and therapeutic response in the post-treatment era. In this article, we review the evidence base to address these challenges. The key factors that determine individual treatment choice and response are discussed. The changed clinical characteristics in treated children that need early identification and appropriate management are discussed in depth. A new classification system in keeping with the changed paradigm is provided. In these early times of the treatment era, the evidence from clinical trials and real world is combined to generate evidence base to guide management. The reader would be apprised of the recent therapeutic developments, their applications, and outcomes. Finally, the challenges to be expected along the uncharted path of prolonged lifespan are discussed and care guidelines provided.