Nusinersen as a Therapeutic Agent for Spinal Muscular Atrophy
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초록
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.
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.
참고문헌 (82)
- Hua Y, "Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model", Genes Dev, 24, pp.1634~1644 (2010)
- Singh NK, "Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron", Mol Cell Biol, 26, pp.1333~1346 (2006)
- Wan L, "The survival of motor neurons protein determines the capacity for snRNP assembly : biochemical deficiency in spinal muscular atrophy", Mol Cell Biol, 25, pp.5543~5551 (2005)
- Hua Y, "Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon", PLoS Biol, 5, pp.e73~ (2007)
- Kashima T, "A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy", Nat Genet, 34, pp.460~463 (2003)
- Cartegni L, "Disruption of an SF2", ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1, 2002, pp.30, 377~384
- Lunn MR, "Spinal muscular atrophy", Lancet, 371, pp.2120~2133 (2008)
- Foust KD, "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN", Nat Biotechnol, 28, pp.271~274 (2010)
- Coady TH, "Restoration of SMN function : delivery of a trans-splicing RNA re-directs SMN2 premRNA splicing", Mol Ther, 15, pp.1471~1478 (2007)
- Madocsai C, "Correction of SMN2Pre-mRNA splicing by antisense U7 small nuclear RNAs", Mol Ther, 12, pp.1013~1022 (2005)
- Khorkova O, "Oligonucleotide therapies for disorders of the nervous system", Nat Biotechnol, 35, pp.249~263 (2017)
- Farr SA, "Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576(AβPPswe)mice", J Alzheimers Dis, 40, pp.1005~1016 (2014)
- Juliano RL, "The delivery of therapeutic oligonucleotides", Nucleic Acids Res, 44, pp.6518~6548 (2016)
- Eckstein F, "Nucleoside phosphorothioates", J Am Chem Soc, 92, pp.4718~4723 (1970)
- Bobst AM, "Effect of the methylation of the 2’-hydroxyl groups in polyadenylic acid on its structure in weakly acidic and neutral solutions and on its capability to form ordered complexes with polyuridylic acid", J Mol Biol, 46, pp.221~234 (1969)
- Evers MM, "Antisense oligonucleotides in therapy for neurodegenerative disorders", Adv Drug Deliv Rev, 87, pp.90~103 (2015)
- Hua Y, "Antisense masking of an hnRNP A1", A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice, 2008, pp.82, 834~848
- Rigo F, "Antisense-based therapy for the treatment of spinal muscular atrophy", J Cell Biol, 199, pp.21~25 (2012)
- Juliano RL, "Cellular uptake and intracellular trafficking of antisense and siRNA oligonucleotides", Bioconjug Chem, 23, pp.147~157 (2012)
- Koller E, "Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes", Nucleic Acids Res, 39, pp.4795~4807 (2011)
- Wagenaar TR, "Identification of the endosomal sorting complex required for transport-I(ESCRT-I)as an important modulator of anti-miR uptake by cancer cells", Nucleic Acids Res, 43, pp.1204~1215 (2015)
- Liang XH, "Hsp90 protein interacts with phosphorothioate oligonucleotides containing hydrophobic 2’-modifications and enhances antisense activity", Nucleic Acids Res, 44, pp.3892~3907 (2016)
- Shemesh CS, "Pharmacokinetic and pharmacodynamic investigations of ION-353382, a model antisense oligonucleotide : using alpha-2-macroglobulin and murinoglobulin double-knockout mice", Nucleic Acid Ther, 26, pp.223~235 (2016)
- Shen W, "Phosphorothioate oligonucleotides can displace NEAT1 RNA and form nuclear paraspeckle-like structures", Nucleic Acids Res, 42, pp.8648~8662 (2014)
- Liang XH, "TCP1 complex proteins interact with phosphorothioate oligonucleotides and can co-localize in oligonucleotide-induced nuclear bodies in mammalian cells", Nucleic Acids Res, 42, pp.7819~7832 (2014)
- Liang XH, "Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages", Nucleic Acids Res, 43, pp.2927~2945 (2015)
- Ezzat K, "Scavenger receptor-mediated uptake of cell-penetrating peptide nanocomplexes with oligonucleotides", FASEB J, 26, pp.1172~1180 (2012)
- Ugarte-Uribe B, "Synthesis, cell-surface binding, and cellular uptake of fluorescently labeled glucose-DNA conjugates with different carbohydrate presentation", Bioconjug Chem, 21, pp.1280~1287 (2010)
- Cheng CJ, "Enhanced siRNA delivery into cells by exploiting the synergy between targeting ligands and cell-penetrating peptides", Biomaterials, 32, pp.6194~6203 (2011)
- Alam MR, "Intracellular delivery of an anionic antisense oligonucleotide via receptor-mediated endocytosis", Nucleic Acids Res, 36, pp.2764~2776 (2008)
- Juliano RL, "Receptors, endocytosis, and trafficking : the biological basis of targeted delivery of antisense and siRNA oligonucleotides", J Drug Target, 21, pp.27~43 (2013)
- Juliano RL, "Cellular uptake and intracellular trafficking of oligonucleotides : implications for oligonucleotide pharmacology", Nucleic Acid Ther, 24, pp.101~113 (2014)
- Sahay G, "Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling", Nat Biotechnol, 31, pp.653~658 (2013)
- Ming X, "Intracellular delivery of an antisense oligonucleotide via endocytosis of a G protein-coupled receptor", Nucleic Acids Res, 38, pp.6567~6576 (2010)
- Miller CM, "Stabilin-1 and Stabilin-2 are specific receptors for the cellular internalization of phosphorothioate-modified antisense oligonucleotides(ASOs)in the liver", Nucleic Acids Res, 44, pp.2782~2794 (2016)
- Kortylewski M, "In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses", Nat Biotechnol, 27, pp.925~932 (2009)
- Shi F, "Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnover", J Cell Sci, 121(Pt 14), pp.2360~2371 (2008)
- Juliano RL, "Cellular uptake and intracellular trafficking of oligonucleotides", Adv Drug Deliv Rev, 87, pp.35~45 (2015)
- Reyes-Reyes EM, "A new paradigm for aptamer therapeutic AS1411 action : uptake by macropinocytosis and its stimulation by a nucleolin-dependent mechanism", Cancer Res, 70, pp.8617~8629 (2010)
- Ezzat K, "Self-assembly into nanoparticles is essential for receptor mediated uptake of therapeutic antisense oligonucleotides", Nano Lett, 15, pp.4364~4373 (2015)
- Kotula JW, "Aptamer-mediated delivery of splice-switching oligonucleotides to the nuclei of cancer cells", Nucleic Acid Ther, 22, pp.187~195 (2012)
- Wang S, "Annexin A2 facilitates endocytic trafficking of antisense oligonucleotides", Nucleic Acids Res, 44, pp.7314~7330 (2016)
- Prakash TP, "Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice", Nucleic Acids Res, 42, pp.8796~8807 (2014)
- Vickers TA, "Development of a quantitative BRET affinity assay for nucleic acid-protein interactions", PLoS One, 11, pp.e0161930~ (2016)
- Castanotto D, "A cytoplasmic pathway for gapmer antisense oligonucleotide-mediated gene silencing in mammalian cells", Nucleic Acids Res, 43, pp.9350~9361 (2015)
- Lorenz P, "Phosphorothioate antisense oligonucleotides induce the formation of nuclear bodies", Mol Biol Cell, 9, pp.1007~1023 (1998)
- Kubo T, "Controlled intracellular localization and enhanced antisense effect of oligonucleotides by chemical conjugation", Org Biomol Chem, 3, pp.3257~3259 (2005)
- Marcusson EG, "Phosphorothioate oligodeoxyribonucleotides dissociate from cationic lipids before entering the nucleus", Nucleic Acids Res, 26, pp.2016~2023 (1998)
- Zelphati O, "Mechanism of oligonucleotide release from cationic liposomes", Proc Natl Acad Sci U S A, 93, pp.11493~11498 (1996)
- Naganuma T, "Paraspeckle formation during the biogenesis of long non-coding RNAs", RNA Biol, 10, pp.456~461 (2013)
- Lorenz P, "Nucleocytoplasmic shuttling : a novel in vivo property of antisense phosphorothioate oligodeoxynucleotides", Nucleic Acids Res, 28, pp.582~592 (2000)
- Doherty GJ, "Mechanisms of endocytosis", Annu Rev Biochem, 78, pp.857~902 (2009)
- Stein CA, "Efficient gene silencing by delivery of locked nucleic acid antisense oligonucleotides, unassisted by transfection reagents", Nucleic Acids Res, 38, pp.e3~ (2010)
- Torres AG, "Potent and sustained cellular inhibition of miR-122 by lysine-derivatized peptide nucleic acids(PNA)and phosphorothioate locked nucleic acid(LNA)", 2'-Omethyl(OMe)mixmer anti-miRs in the absence of transfection agents, 2011, pp.2, 71~78
- Smith RA, "Antisense oligonucleotide therapy for neurodegenerative disease", J Clin Invest, 116, pp.2290~2296 (2006)
- Wahlestedt C, "Antisense oligodeoxynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischaemic infarctions", Nature, 363, pp.260~263 (1993)
- Wahlestedt C, "Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides", Science, 259, pp.528~531 (1993)
- Wahlestedt C, "Antisense oligonucleotide strategies in neuropharmacology", Trends Pharmacol Sci, 15, pp.42~46 (1994)
- Standifer KM, "Selective loss of delta opioid analgesia and binding by antisense oligodeoxynucleotides to a delta opioid receptor", Neuron, 12, pp.805~810 (1994)
- Pechmann A, "Single-center experience with intrathecal administration of nusinersen in children with spinal muscular atrophy type 1", Eur J Paediatr Neurol, 22, pp.122~127 (2018)
- Zanetta C, "Molecular therapeutic strategies for spinal muscular atrophies : current and future clinical trials", Clin Ther, 36, pp.128~140 (2014)
- Passini MA, "Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy", Sci Transl Med, 3, pp.72ra18~ (2011)
- Geary RS, "Antisense oligonucleotide pharmacokinetics and metabolism", Expert Opin Drug Metab Toxicol, 5, pp.381~391 (2009)
- Rigo F, "Pharmacology of a central nervous system delivered 2'-O-methoxyethylmodified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates", J Pharmacol Exp Ther, 350, pp.46~55 (2014)
- Heemskerk H, "Preclinical PK and PD studies on 2'-O-methylphosphorothioate RNA antisense oligonucleotides in the mdx mouse model", Mol Ther, 18, pp.1210~1217 (2010)
- Verhaart IE, "Dose-dependent pharmacokinetic profiles of 2'-O-methyl phosphorothioate antisense oligonucleotidesin mdx mice", Nucleic Acid Ther, 23, pp.228~237 (2013)
- Kordasiewicz HB, "Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis", Neuron, 74, pp.1031~1044 (2012)
- Geary RS, "Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides", Adv Drug Deliv Rev, 87, pp.46~51 (2015)
- Chiriboga CA, "Results from a phase 1 study of nusinersen(ISISSMN(Rx))in children with spinal muscular atrophy", Neurology, 86, pp.890~897 (2016)
- Haché M, "Intrathecal injections in children with spinal muscular atrophy : nusinersen clinical trial experience", J Child Neurol, 31, pp.899~906 (2016)
- Engelhardt JA, "Comparative renal toxicopathology of antisense oligonucleotides", Nucleic Acid Ther, 26, pp.199~209 (2016)
- Matsuzawa J, "Age-related volumetric changes of brain gray and white matter in healthy infants and children", Cereb Cortex, 11, pp.335~342 (2001)
- Finkel RS, "Treatment of infantile-onset spinal muscular atrophy with nusinersen : a phase 2, open-label, dose-escalation study", Lancet, 388, pp.3017~3026 (2016)
- Frisone MF, "Prognostic value of the neurologic optimality score at 9 and 18 months in preterm infants born before 31 weeks’ gestation", J Pediatr, 140, pp.57~60 (2002)
- Glanzman AM, "The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders(CHOP INTEND) : test development and reliability", Neuromuscul Disord, 20, pp.155~161 (2010)
- Yu RZ, "Development of an ultrasensitive noncompetitive hybridization-ligation enzyme-linked immunosorbent assay for the determination of phosphorothioate oligodeoxynucleotide in plasma", Anal Biochem, 304, pp.19~25 (2002)
- Finkel RS, "Nusinersen versus sham control in infantile-onset spinal muscular atrophy", N Engl J Med, 377, pp.1723~1732 (2017)
- Mercuri E, "Nusinersen versus sham control in later-onset spinal muscular atrophy", N Engl J Med, 378, pp.625~635 (2018)
- Glanzman AM, "Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III", J Child Neurol, 26, pp.1499~1507 (2011)
- O’Hagen JM, "An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients", Neuromuscul Disord, 17, pp.693~697 (2007)
- Ebinger F, "Headache and backache after lumbar puncture in children and adolescents : a prospective study", Pediatrics, 113, pp.1588~1592 (2004)
- Morgenlander JC, "Lumbar puncture and CSF examination. Answers to three commonly asked questions", Postgrad Med, 95, pp.125~128 (1994)
