Top

Published in:

Open Access 01-12-2018 | Review

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases

Authors: Kelly M. Martinovich, Nicole C. Shaw, Anthony Kicic, André Schultz, Sue Fletcher, Steve D. Wilton, Stephen M. Stick

Published in: Molecular and Cellular Pediatrics | Issue 1/2018

Abstract

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient’s genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.

Stein CA, Castanotto D (2017) FDA-approved oligonucleotide therapies in 2017. Mol Ther. 25(5): p. 1069–1075

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. U.S. Food and Drug Administration news release 19th September 2016; Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm521263.htm

FDA approves first drug for spinal muscular atrophy. U.S. Food and Drug Administration news release 23 December 2016; Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm534611.htm

Sterne-Weiler T, Sanford JR (2014) Exon identity crisis: disease-causing mutations that disrupt the splicing code. Genome Biol 15(1):201–201CrossRefPubMedPubMedCentral

Chan JH, Lim S, Wong WS (2006) Antisense oligonucleotides: from design to therapeutic application. Clin Exp Pharmacol Physiol 33(5–6):533–540CrossRefPubMed

Khvorova A, Watts JK (2017) The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotech 35(3):238–248CrossRef

Evers MM, Toonen LJ, van Roon-Mom WM (2015) Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev 87:90–103CrossRefPubMed

McGarry ME et al (2017) In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N-of-1 studies. Pediatr Pulmonol 52(4):472–479CrossRefPubMedPubMedCentral

Lillie EO et al (2011) The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Per Med 8(2):161–173CrossRefPubMedPubMedCentral

10.

Williamson SF et al (2017) A Bayesian adaptive design for clinical trials in rare diseases. Comput Statist Data Anal 113(Supplement C):136–153CrossRef

11.

Schmidli H, Neuenschwander B, Friede T (2017) Meta-analytic-predictive use of historical variance data for the design and analysis of clinical trials. Comput Stat Data Anal 113(Supplement C):100–110CrossRef

12.

Crooke ST (2013) RNA directed therapeutics: mechanisms and status. Drug Discov Today Therapeutic Strateg 10(3):e109–e117CrossRef

13.

Crooke ST et al (2016) Integrated safety assessment of 2′-O-methoxyethyl chimeric antisense oligonucleotides in nonhuman primates and healthy human volunteers. Mol Ther 24(10):1771–1782CrossRefPubMedPubMedCentral

14.

Burdick AD et al (2014) Sequence motifs associated with hepatotoxicity of locked nucleic acid—modified antisense oligonucleotides. Nucleic Acids Res 42(8):4882–4891CrossRefPubMedPubMedCentral

15.

Shen X, Corey DR (2017) Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. [Epub ahead of print]

16.

Jarver P, O'Donovan L, Gait MJ (2014) A chemical view of oligonucleotides for exon skipping and related drug applications. Nucleic Acid Ther 24(1):37–47CrossRefPubMedPubMedCentral

17.

Bennett CF, Swayze EE (2010) RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 50:259–293CrossRefPubMed

18.

Dias N, Stein CA (2002) Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 1(5):347–355PubMed

19.

Agrawal S et al (1995) Pharmacokinetics of antisense oligonucleotides. Clin Pharmacokinet 28(1):7–16CrossRefPubMed

20.

Kole R, Vacek M, Williams T (2004) Modification of alternative splicing by antisense therapeutics. Oligonucleotides 14(1):65–74CrossRefPubMed

21.

Havens MA, Hastings ML (2016) Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res 44(14):6549–6563CrossRefPubMedPubMedCentral

22.

Stephenson ML, Zamecnik PC (1978) Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci U S A 75(1):285–288CrossRefPubMedPubMedCentral

23.

Donis-Keller H (1979) Site specific enzymatic cleavage of RNA. Nucleic Acids Res 7(1):179–192CrossRefPubMedPubMedCentral

24.

Roehr B (1998) Fomivirsen approved for CMV retinitis. J Int Assoc Physicians AIDS Care 4(10):14–6

25.

Wathion, N. (2002) Public statement on Vitravene (fomivirsen). The European Agency for the Evaluation of Medical Products [cited 6th August 2002; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/12/WC500018346.pdf. Cited on 19 July 2017

26.

Ng EWM et al (2006) Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5(2):123–132CrossRefPubMed

27.

Wong E, Goldberg T (2014) Mipomersen (Kynamro): a novel antisense oligonucleotide inhibitor for the management of homozygous familial hypercholesterolemia. Pharm Ther 39(2):119–122

28.

Dominski Z, Kole R (1993) Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci U S A 90(18):8673–8677CrossRefPubMedPubMedCentral

29.

Lacerra G et al (2000) Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients. Proc Natl Acad Sci U S A 97(17):9591–9596CrossRefPubMedPubMedCentral

30.

Kipshidze NN et al (2002) Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model. J Am Coll Cardiol 39(10):1686–1691CrossRefPubMed

31.

Moreno PM, Pego AP (2014) Therapeutic antisense oligonucleotides against cancer: hurdling to the clinic. Front Chem 2:87CrossRefPubMedPubMedCentral

32.

Castanotto D, Stein CA (2014) Antisense oligonucleotides in cancer. Curr Opin Oncol 26(6):584–589CrossRefPubMed

33.

Riboldi G et al (2014) Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases. Mol Neurobiol 50(3):721–732CrossRefPubMed

34.

Aronin N, DiFiglia M (2014) Huntingtin-lowering strategies in Huntington’s disease: antisense oligonucleotides, small RNAs, and gene editing. Mov Disord 29(11):1455–1461CrossRefPubMed

35.

Greer KL et al (2014) Targeted exon skipping to correct exon duplications in the dystrophin gene. Mol Ther Nucleic Acids 3:e155CrossRefPubMedPubMedCentral

36.

Kinane TB, et al (2017) Long-term pulmonary function in Duchenne muscular dystrophy: comparison of eteplirsen-treated patients to natural history. J Neuromuscul Dis. [Epub ahead of print]

37.

Sarepta Therapeutics, I., (2017) Sarepta Therapeutics announces positive results in its study evaluating gene expression, dystrophin production, and dystrophin localization in patients with Duchenne muscular dystrophy (DMD) amenable to skipping exon 53 treated with golodirsen (SRP-4053), I. Estepan, Editor.: http://investorrelations.sarepta.com

38.

Yokota T et al (2007) Potential of oligonucleotide-mediated exon-skipping therapy for Duchenne muscular dystrophy. Expert Opin Biol Ther 7(6):831–842CrossRefPubMed

39.

Adkin CF et al (2012) Multiple exon skipping strategies to by-pass dystrophin mutations. Neuromuscul Disord 22(4):297–305CrossRefPubMedPubMedCentral

40.

Miskew Nichols B et al (2016) Multi-exon skipping using cocktail antisense oligonucleotides in the canine X-linked muscular dystrophy. J Vis Exp 111:53776

41.

Wilton SD et al (2007) Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript. Mol Ther 15(7):1288–1296CrossRefPubMed

42.

Béroud C et al (2007) Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum Mutat 28(2):196–202CrossRefPubMed

43.

Lefebvre S et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80(1):155–165CrossRefPubMed

44.

Lorson CL et al (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci 96(11):6307–6311CrossRefPubMedPubMedCentral

45.

Singh NK et al (2006) 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(4):1333–1346CrossRefPubMedPubMedCentral

46.

Finkel RS et al (2016) Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388(10063):3017–3026CrossRefPubMed

47.

Paton DM (2017) Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy. Drugs Today (Barc) 53(6):327–337CrossRef

48.

Ferec C, Cutting GR (2012) Assessing the disease-liability of mutations in CFTR. Cold Spring Harb Perspect Med 2(12):a009480CrossRefPubMedPubMedCentral

49.

Kreindler JL (2010) Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. Pharmacol Ther 125(2):219–229CrossRefPubMed

50.

Rommens DJM (2011) CFTR Mutation Database. Hospital for Sick Children

51.

Welsh MJ, Smith AE (1993) Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73(7):1251–1254CrossRefPubMed

52.

Accurso FJ et al (2010) Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 363(21):1991–2003CrossRefPubMedPubMedCentral

53.

Van Goor F et al (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci 106(44):18825–18830CrossRefPubMedPubMedCentral

54.

Wainwright CE et al (2015) Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373(3):220–231CrossRefPubMedPubMedCentral

55.

Beumer W et al (2015) WS01.2 QR-010, an RNA therapy, restores CFTR function using in vitro and in vivo models of ΔF508 CFTR. J Cyst Fibros 14:S1CrossRef

56.

Zamecnik PC et al (2004) Reversal of cystic fibrosis phenotype in a cultured Delta508 cystic fibrosis transmembrane conductance regulator cell line by oligonucleotide insertion. Proc Natl Acad Sci U S A 101(21):8150–8155CrossRefPubMedPubMedCentral

57.

Massie RJ et al (2001) Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Eur Respir J 17(6):1195–1200CrossRefPubMed

58.

Radpour R et al (2007) Molecular study of (TG)m(T)n polymorphisms in Iranian males with congenital bilateral absence of the vas deferens. J Androl 28(4):541–547CrossRefPubMed

59.

Chu CS et al (1991) Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium. EMBO J 10(6):1355–1363PubMedPubMedCentral

60.

Igreja S et al (2016) Correction of a cystic fibrosis splicing mutation by antisense oligonucleotides. Hum Mutat 37(2):209–215CrossRefPubMed

61.

Quint A et al (2005) Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am J Med Genet A 136(3):246–248CrossRefPubMed

62.

Friedman KJ et al (1999) Correction of aberrant splicing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by antisense oligonucleotides. J Biol Chem 274(51):36193–36199CrossRefPubMed

63.

Highsmith WE et al (1994) A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 331(15):974–980CrossRefPubMed

64.

Griese M (1999) Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J 13(6):1455–1476CrossRefPubMed

65.

Wert SE, Whitsett JA, Nogee LM (2009) Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol 12(4):253–274CrossRefPubMedPubMedCentral

66.

Whitsett JA, Wert SE, Weaver TE (2015) Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol 10:371–393CrossRefPubMedPubMedCentral

67.

Gupta A, Zheng SL (2017) Genetic disorders of surfactant protein dysfunction: when to consider and how to investigate. Arch Dis Child 102(1):84–90CrossRefPubMed

68.

Gower WA, Nogee LM (2011) Surfactant dysfunction. Paediatr Respir Rev 12(4):223–229CrossRefPubMedPubMedCentral

69.

Faro A, Hamvas A (2008) Lung transplantation for inherited disorders of surfactant metabolism. NeoReviews 9(10):e468–e476CrossRef

70.

Hamvas A (2010) Evaluation and management of inherited disorders of surfactant metabolism. Chin Med J 123(20):2943–2947PubMed

71.

Williamson M, Wallis C (2014) Ten-year follow up of hydroxychloroquine treatment for ABCA3 deficiency. Pediatr Pulmonol 49(3):299–301CrossRefPubMed

72.

Don Hayes J et al (2012) ABCA3 transporter deficiency. Am J Respir Crit Care Med 186(8):807–807CrossRefPubMed

73.

de Benedictis FM, Bush A (2012) Corticosteroids in respiratory diseases in children. Am J Respir Crit Care Med 185(1):12–23CrossRefPubMed

74.

Wambach JA et al (2014) Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 189(12):1538–1543CrossRefPubMedPubMedCentral

75.

Agrawal A et al (2012) An intronic ABCA3 mutation that is responsible for respiratory disease. Pediatr Res 71(6):633–637CrossRefPubMedPubMedCentral

76.

Nogee LM (2002) Abnormal expression of surfactant protein C and lung disease. Am J Respir Cell Mol Biol 26(6):641–644CrossRefPubMed

77.

Wang W-J et al (2002) Biosynthesis of surfactant protein C (SP-C): sorting of SP-C proprotein involves homomeric association via a signal anchor domain. J Biol Chem 277(22):19929–19937CrossRefPubMed

78.

Mulugeta S et al (2005) A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am J Respir Cell Mol Biol 32(6):521–530CrossRefPubMedPubMedCentral

79.

Geary RS et al (2015) Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev 87:46–51CrossRefPubMed

80.

Moschos SA et al (2011) Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense. Mol Ther 19(12):2163–2168CrossRefPubMedPubMedCentral

81.

Moschos SA et al (2008) Targeting the lung using siRNA and antisense based oligonucleotides. Curr Pharm Des 14(34):3620–3627CrossRefPubMed

82.

Moschos SA, Usher L, Lindsay MA (2017) Clinical potential of oligonucleotide-based therapeutics in the respiratory system. Pharmacol Ther 169:83–103CrossRefPubMed

83.

Fey RA et al (2014) Local and systemic tolerability of a 2′O-methoxyethyl antisense oligonucleotide targeting interleukin-4 receptor-alpha delivery by inhalation in mouse and monkey. Inhal Toxicol 26(8):452–463CrossRefPubMed

84.

Karras JG et al (2007) Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice. Am J Respir Cell Mol Biol 36(3):276–285CrossRefPubMed

85.

Lach-Trifilieff E et al (2001) In vitro and in vivo inhibition of interleukin (IL)-5-mediated eosinopoiesis by murine IL-5Ralpha antisense oligonucleotide. Am J Respir Cell Mol Biol 24(2):116–122CrossRefPubMed

86.

Duan W et al (2005) Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med 171(6):571–578CrossRefPubMed

87.

Crosby JR et al (2007) Inhaled CD86 antisense oligonucleotide suppresses pulmonary inflammation and airway hyper-responsiveness in allergic mice. J Pharmacol Exp Ther 321(3):938–946CrossRefPubMed

88.

Yin H et al (2014) Non-viral vectors for gene-based therapy. Nat Rev Genet 15(8):541–555CrossRefPubMed

89.

Mologni L, Nielsen PE, Gambacorti-Passerini C (1999) In vitro transcriptional and translational block of the bcl-2 gene operated by peptide nucleic acid. Biochem Biophys Res Commun 264(2):537–543CrossRefPubMed

90.

Zhao J, Feng SS (2015) Nanocarriers for delivery of siRNA and co-delivery of siRNA and other therapeutic agents. Nanomedicine (Lond) 10(14):2199–2228CrossRef

91.

Yang Q et al (2014) Evading immune cell uptake and clearance requires PEG grafting at densities substantially exceeding the minimum for brush conformation. Mol Pharm 11(4):1250–1258CrossRefPubMed

92.

Juliano RL (2016) The delivery of therapeutic oligonucleotides. Nucleic Acids Res 44(14):6518–6548CrossRefPubMedPubMedCentral

93.

Ugarte-Uribe B, et al (2016) Lipid-modified oligonucleotide conjugates: insights into gene silencing, interaction with model membranes and cellular uptake mechanisms. Bioorg Med Chem 25(1):175–186

94.

Alam MR et al (2008) Intracellular delivery of an anionic antisense oligonucleotide via receptor-mediated endocytosis. Nucleic Acids Res 36(8):2764–2776CrossRefPubMedPubMedCentral

95.

Dassie JP, Giangrande PH (2013) Current progress on aptamer-targeted oligonucleotide therapeutics. Ther Deliv 4(12):1527–1546CrossRefPubMedPubMedCentral

96.

Lu QL et al (2003) Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med 9(8):1009–1014CrossRefPubMed

97.

Han G et al (2016) Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice. Nat Commun 7:10981CrossRefPubMedPubMedCentral

98.

Crooke ST et al (2017) Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol 35(3):230–237CrossRefPubMed

Title: The potential of antisense oligonucleotide therapies for inherited childhood lung diseases
Authors: Kelly M. Martinovich
Nicole C. Shaw
Anthony Kicic
André Schultz
Sue Fletcher
Steve D. Wilton
Stephen M. Stick
Publication date: 01-12-2018
Publisher: Springer Berlin Heidelberg
Published in: Molecular and Cellular Pediatrics / Issue 1/2018
Electronic ISSN: 2194-7791
DOI: https://doi.org/10.1186/s40348-018-0081-6

At a glance: The STEP trials

Springer Medicine

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2018

Anti-inflammatory monocytes—interplay of innate and adaptive immunity

Precision medicine in pediatric oncology

Intrauterine growth restriction - impact on cardiovascular diseases later in life

Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis

The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases

CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility