Yonsei Med J.  2020 Apr;61(4):273-283. 10.3349/ymj.2020.61.4.273.

Nusinersen as a Therapeutic Agent for Spinal Muscular Atrophy

• Li Q

• KMID: 2471912
• DOI: http://doi.org/10.3349/ymj.2020.61.4.273

Abstract

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.

Keyword

blood-brain barrier; cellular uptake; exon splicing; phosphonothioate antisense oligonucleotides; survival of motor neuron gene; Nusinersen

MeSH Terms

Blood-Brain Barrier
Central Nervous System
Drug Delivery Systems
Exons
Motor Neurons
Muscular Atrophy, Spinal*
Neuromuscular Diseases
Pharmacokinetics

Figure

• 

  Fig. 1 Oligonucleotide uptake and trafficking in cells. It has been proposed that phosphonothioate antisense oligonucleotides (PS-ASOs) enter cells via two pathways: productive pathway and non-productive pathway. Productive pathway guides PS-ASOs to access their targets (yellow outlines), and non-productive pathways sequester PS-ASOs in saturable sinks (blue outlines). Uptake and internalization of PS-ASOs can be directed by cell-surface proteins (including receptors) through caveolin- or clathrin-dependent pathways or other pathways of endocytosis. The endocytosis vesicle bud from the membrane and the scission of the plasma membrane is catalyzed by GTPase dynamin. Freed cargo-containing vesicles with PS-ASOs fuse with early endosomes (EE) by being transported along the cytoskeletal structures of tubulin or actin. Internalized ASOs can be transported from EE to late endosomes (LE) and to lysosomes. PS-ASOs predominately accumulate in punctate structures in EE, LE, lysosomes (possibly equal to phosphonothioate bodies of cytoplasm), and Golgi-58K-related vesicles, in which non-productive and productive pathways of uptake may diverge and the majority of oligonucleotides are likely reserved in non-productive pathway. A small number of PS-ASOs can be released from endosomal organelles and escape into productive pathway, involving entry into the nucleus and cytosol to act on target DNA. Entering into the nucleus is likely via the RAN-mediated pathway. PS-ASOs may be linked to paraspeckle proteins in the nucleus and shape functional paraspeckle-like structures.

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