History of development of the life-saving drug “Nusinersen” in spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with an incidence of 1/6,000–1/10,000 and is the leading fatal disease among infants. Previously, there was no effective treatment for SMA. The first effective drug, nusinersen, was approved by the US FDA in December 2016, providing hope to SMA patients worldwide. The drug was introduced in the European Union in 2017 and China in 2019 and has so far saved the lives of several patients in most parts of the world. Nusinersen are fixed sequence antisense oligonucleotides with special chemical modifications. The development of nusinersen progressed through major scientific discoveries in medicine, genetics, biology, and other disciplines, wherein several scientists have made substantial contributions. In this article, we will briefly describe the pathogenesis and therapeutic strategies of SMA, summarize the timeline of important scientific findings during the development of nusinersen in a detailed, scientific, and objective manner, and finally discuss the implications of the development of nusinersen for SMA research.

Administration of adipose-derived stem cells extracellular vesicles in a murine model of spinal muscular atrophy: effects of a new potential therapeutic strategy

“…The pathogenesis of SMA is linked to the deficiency of the full-length SMN protein due to deletion or mutation on the SMN1 gene. Several SMN-dependent therapeutic strategies have been exploited to restore the level of SMN by correcting the SMN2 gene splicing as both Nusinersen (Spinraza, Biogen) and Risdiplam (Evrysdi, Roche) [ 58 , 59 ] or by delivering a functional copy of SMN1 gene into cells for its expression, as Onasemnogene abeparvovec (Zolgensma, Novartis) [ 60 ]. Besides the remarkable results obtained with these approved drugs, some issues and limitations remain, such as still unknown long-term effects, the possible treatment-related toxicity, and the high cost of these therapies.…”

Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing

“…Antisense oligonucleotides (AONs) are an increasingly appealing therapeutic strategy to clinically modulate alternative splicing, as recently illustrated by the clinical success of Nusinersen for the treatment of Spinal Muscular Atrophy 16 and Eteplirsen for Duchenne muscular dystrophy 17 . AONs base-pair to splice sites or regulatory sequences, competing with the binding of splicing factors and regulators 63 .…”

“…The frequent disruption of splicing in human disease has led to extensive efforts to therapeutically modulate splicing 15 . In particular, antisense oligonucleotides (AONs) that modulate splicing have been approved as therapies for spinal muscular atrophy 16 and Duchenne muscular dystrophy 17 . Indeed AONs – because of their programmable sequence specificity – may represent a general strategy to therapeutically modulate many splicing changes 18 .…”

The Strategies for the Treatment of Spinal Muscular Atrophy

“…Qiu J, Wu L, Qu R, Jiang T, Bai J, Sheng L, Feng P, Sun J (2022) 26 History of development of the life-saving drug "Nusinersen" in spinal muscular atrophy.…”