Skip to main content
SpringerLink
Log in

Eteplirsen

  • Chapter
  • First Online:
Molecular Basis of Resilience

  • 462 Accesses

Abstract

Once we observed alternate exon use in the mouse model of Duchene Muscular Dystrophy, the basis for molecular resilience was established. The application of antisense oligomers to enhance resilience was set in motion. Manipulation of exon exclusion/inclusion for therapeutic benefit in individuals with rare genetic diseases holds broad potential.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    This is an inside joke since generic drug names should not contain recognizable references. The naming committee acknowledged my role in creating the project while recognizing my role being edged out by new management.

  2. 2.

    The closure of the Corvallis site and termination notices for the staff was done by teleconference from Boston. The CEO wanted to wish well by saying, “Go Buckeyes” as a reference to Ohio State University. He apparently did not know that Oregon State University, also OSU, located in Corvallis mascot is the Beavers.

  3. 3.

    An embarrassing response since no drug is required for a placebo group.

References

  • Alter J, Lou F, Rabinowitz A, Yin H, Rosenfeld J, Wilton SD, Partridge TA, Lu Q. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med. 2006;12(2):175–7.

    Article  CAS  Google Scholar 

  • Bayever E, Iversen P, Smith L, Spinolo J, Zon G. Guest editorial: systemic human antisense therapy begins. Antisense Res Dev. 1992;2:109–10.

    Article  CAS  Google Scholar 

  • Bayever E, Iversen PL, Bishop M, Sharp JG, Tewary HK, Arneson MA, Pirruccello SJ, Ruddon RW, Kessinger A, Zon G, Armitage JO. Systemic administration of a phosphorothioate oligonucleotide with a sequence complementary to p53 for acute myelogenous leukemia and myelodysplastic syndrome: initial results of a phase I trial. Antisense Res Dev. 1993;3:383–90.

    Article  CAS  Google Scholar 

  • Becker PE, Kiener F. Eine neue X-chromosomale Muskel-Dystrophie. Arch Psychiatr Nerveenkr. 1955;193:427–48.

    Article  CAS  Google Scholar 

  • Bell C. The nervous system of the human body: as explained in a series of papers read before the Roal Society of London. Edinburgh: Adam & Charles Black; 1830.

    Google Scholar 

  • Berget SM, Moore C, Sharp PA. Spiced segments at the 5′ terminus of adenovirus 2 late mRNA. Proc Natl Acad Sci U S A. 1977;74(8):3171–5.

    Article  CAS  Google Scholar 

  • Brioschi S, Gualandi F, Scotton C, Armaroli A, Bovolenta M, Falzarano MS, Sabatelli P, Selvatici R, D’Amico A, Aane M, Ricci G, Siciliano G, Tedeschi S, Pini A, Vercelli L, DeGrandis D, Mercuri E, Bertini E, Merlini L, Mongini T, Ferlini A. Gene characterization in symptomiatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype. BMC Med Genet. 2012;13:73.

    Article  CAS  Google Scholar 

  • Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label,phase 2, dose-escalation study. Lancet. 2011;378:595–605.

    Article  CAS  Google Scholar 

  • Conte G, Gioja L. Scrofola del Sistema muscolare. Annali Clinici dell’Ospedale degli Icurabili di Napoli. 1836;2:66–79.

    Google Scholar 

  • Cornish KG, Iversen PL, Smith LJ, Arneson MA, Bayever E. Cardiovascular effects of a phosphorothioate oligonucleotide with sequence antisense to p53 in the concious rhesus monkey. Pharmacol Commun. 1993;3:239–47.

    CAS  Google Scholar 

  • Doninski Z, Kole R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci U S A. 1993;90:8673–7.

    Article  Google Scholar 

  • Duchenne GBA. De l’electrisation localisee et son application a la pathologie et a la therapeutique. 2nd ed. Paris: Bailliere et fils; 1861.

    Google Scholar 

  • Duchenne GBA. Researches sur la paralysie musculaire pseudohypertrophique ou paralysie myo-sclerosique. Arch Gen Med. 1868;11:5–588.

    Google Scholar 

  • Egan W, Boal J, Iyer R, Strom C, Wilson S, Meyer A, Iversen P. Abasic oligodeoxyribonucleotide phosphorothioates as inhibitors of the human immunodeficiency virus-1 (HIV-1): phosphorothioate inhibition of HIV-1 reverse transcriptase and interactions with Syrian hamster fibroblast (V79) cells. Nucleosides Nucleotides. 1991;10(1–3):457–60.

    Article  CAS  Google Scholar 

  • Fall AM, Johnsen R, Honeyman K, Iversen P, Fletcher S, Wilton SD. Induction of revertant fibres in the mdx mouse using antisense oligonucletoides. Genet Vaccin Ther. 2006;4:3–15.

    Article  Google Scholar 

  • Fletcher S, Honeyman K, Fall AM, Harding PL, Johnson RD, Steinhaus JP, Moulton HM, Iversen PL, Wilton SD. Morpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse. Mol Ther. 2007;15(9):1587–92.

    Article  CAS  Google Scholar 

  • Gebski Bianca L, Mann CJ, Fletcher S, Wilton SD. Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle. Hum Mol Genet. 2003;12(15):1801–11.

    Article  CAS  Google Scholar 

  • Gowers WR. A manual of disease of the nervous system, vol. 1. London: Churchill; 1886. p. 391–4.

    Google Scholar 

  • Griesinger W. Uber Muskelhypertrophie. Arch Heilkd. 1865;6:1–13.

    Google Scholar 

  • Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the product of the duchenne muscular dystrophy locus. Cell. 1987;51(6):919–28.

    Article  CAS  Google Scholar 

  • Hoffman EP, Fischbeck KH, Brown BH, Johnson M, Medori R, Loire JD, Harris JB, Waterston R, Brooke M, Specht L, Kupsky W, Chamberlain J, Caskey CT, Shapiro F, Kunkel LM. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N Engl J Med. 1988;318:1363–8.

    Article  CAS  Google Scholar 

  • Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Leschot NJ, Van Essen AJ, Brunner HG, van der Wow PA, Wilde AA, de Visser M. Sings and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands: a cohort study. Lancet. 1999;353:2116–9.

    Article  CAS  Google Scholar 

  • Hudziak RM, Summerton J, Weller, Iversen PL. Antiproliferative effects of steric blocking phosphorodiamidate Morpholino antisense agents directed against c-myc. Antisense Nucleic Acid Drug Dev. 2000;10:163–76.

    Article  CAS  Google Scholar 

  • Iversen PL, Mata JE, Tracewell WG, Zon G. Pharmacokinetics of an antisense Phosphorothioate Oligodeoxynucleotide against rev from human immunodeficiency virus type 1 in the adult male rat following single injections and continuous infusion. Antisense Res Dev. 1994;4:43–52.

    Article  CAS  Google Scholar 

  • Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, Mcculley C, Popplewell L, Graham IR, Dickson G, Wood MJA, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, Montoni F. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, proof-of-concept study. Lancet Neurol. 2009;8:918–28.

    Article  CAS  Google Scholar 

  • Kunkel LM, Beggs AH, Hoffman EP. Molecular genetics of Duchenne and Becker muscular dystrophy: emphasis on improved diagnosis. Clin Chem. 1989;35(7 suppl):B21–4.

    CAS  PubMed  Google Scholar 

  • Lee Y, Rio DC. Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem. 2015;84:291–323.

    Article  CAS  Google Scholar 

  • Letsinger RL, Ogilvie KK. Nucleotide chemistry. XIII Synthesis of oligothymidates via phosphotriester intermediates. J Am Chem Soc. 1969;91(12):3350–5.

    Article  CAS  Google Scholar 

  • Little WJ. On the nature and treatment of the efomities of the human frame: being a course of lectures delivered at the Royal Orthopaedic Hospital in 1843. London: Longman, Brown, Green & Longmans; 1853. p. 14–6.

    Google Scholar 

  • Lu QL, Rabinowitz A, Chen YC, Yokota T, Yin HF, Alter J, Jadoon A, Bou-Gharios G, Partridge TA. Systemic delivery of antisense oligonucleotide restores dystrophin expression in body-wide skeletal muscles. PNAS. 2005;102(1):198–203.

    Article  CAS  Google Scholar 

  • Mann CJ, Honeyman K, Cheng AJ, Ly T, Lloyd F, Fletcher S, Morgan JE, Partridge TA, Wilton SD. Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc Natl Acad Sci U S A. 2001;98(1):42–7.

    Article  CAS  Google Scholar 

  • Matsukura M, Shinozuka K, Zon G, Mitsuya H, Reitz M, Cohen JS, Broder S. Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus. Proc Natl Acad Sci USA. 1987;84(21):7706–10.

    Article  CAS  Google Scholar 

  • McClorey G, Fall AM, Moulton HM, Iversen PL, Rasko JE, Ryan M, Fletcher S, Wilton SD. Induced dystrophin exon skipping in human muscle explants. Neuromuscul Disord. 2006a;16(9–10):583–90.

    Article  CAS  Google Scholar 

  • McClorey G, Moulton HM, Iversen PL, Fletcher S, Wilton SD. Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD. Gene Ther. 2006b;13(19):1373–81.

    Article  CAS  Google Scholar 

  • Mendell JR, Goemans N, Loes LP, Alfana LN, Berry K, Shao J, Kaye EM, Mercuri E. Longitudinal effect of Eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016;79:257–71.

    Article  CAS  Google Scholar 

  • Meryon E. Practical and pathological researches on the various forms of paralysis. London: Churchill; 1864.

    Google Scholar 

  • Miyagoe-Suzuki Y, Nishiyama T, Nakamura M, Narita A, Takemura S, Minami N, Murayama K, Komaki H, Goto Y, Takeka S. Induction of pluripotent stem cells from a manifesting carrier of Duchenne muscular dystrophy and characterization of their X-inactivation status. Stem Cells Int. 2017;2017:1–9.

    Google Scholar 

  • Moser H, Emery AE. The manifesting carrier in Duchenne muscular dystrophy. Clin Genet. 1974;5(4):271–84.

    Article  CAS  Google Scholar 

  • Nobel Prize in Chemistry 1993 to Kary Mullis.

    Google Scholar 

  • Nobel Prize in Physiology or Medicine 1958 to Geroge Beadle and Edward Tatum.

    Google Scholar 

  • Nobel Prize in Physiology or Medicine 1962 to Crick, Watson and Wilkins.

    Google Scholar 

  • Nobel Prize in Physiology or Medicine 1965 to Francois Jacob, Andre Lwoff, and Jacques Monod.

    Google Scholar 

  • Nobel Prize in Physiology or Medicine 1968 to Holley, Khorana and Nirenberg.

    Google Scholar 

  • Nobel Prize in Physiology or Medicine 1993 to Richard Roberts and Phillip Sharp.

    Google Scholar 

  • Norman A, Harper P. A survey of manifesting carriers of Duchenne and Becker muscular dystrophy in Whales. Clin Genet. 1989;36(1):31–7.

    Article  CAS  Google Scholar 

  • Pena SD, Karpati G, Carpenter S, Fraser FC. The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins. J Neurol Sci. 1987;79(3):337–44.

    Article  CAS  Google Scholar 

  • Pullman S, Mullins B. How the FDA approved a $300,000-a-year drug its own experts didn’t believe worked. Wall Street J. 2017, May 18.

    Google Scholar 

  • Rosenfeld MG, Amara SG, Roos BA, Ong ES, Evans RM. Altered expression of the calcitonin gene associated iwht RNA polymorphism. Nature. 1981;290(5801):63–5.

    Article  CAS  Google Scholar 

  • Sazani P, Weller DL, Shrewsbury SB. Safety pharmacology and genotoxicity evaluation of AVI-4658. Int J Toxicol. 2010:1–14. https://doi.org/10.1177/1091581809359206.

    Article  CAS  Google Scholar 

  • Sazani P, Van Ness KP, Weller DL, Poage DW, Nelson K, Shrewsbury SB. Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice. Int J Toxicol. 2011a:1–12. https://doi.org/10.1177/1091581811403504.

    Article  CAS  Google Scholar 

  • Sazani P, Van Ness KP, Weller DL, Poage DW, Palyada K, Shrewsbury SB. Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of Duchenne muscular dystrophy. Int J Toxicol. 2011b:1–9. https://doi.org/10.1177/1091581811403505.

    Article  CAS  Google Scholar 

  • Stein C, Iversen PL, Subasinghe C, Cohen JS, Zon G. Preparation of 35S-labelled phosphorothioate oligodeoxyribonucleotides by use of hydrogen-phosphonate chemistry. Anal Biochem. 1990;188:11–6.

    Article  CAS  Google Scholar 

  • Stevenson M, Iversen PL. Inhibition of HIV mediated cytopathicityby poly-L-lysine conjugated synthetic antisense oligodeoxyribonucleotides. J Gen Virol. 1989;70:2673–82.

    Article  CAS  Google Scholar 

  • Van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, et al. Local Dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2009;357:2677–86.

    Article  Google Scholar 

  • Wall Street Journal Dec 23, 2016, The FDA Empire Strikes Back.

    Google Scholar 

  • Weatherall DJ. The thalassemias. In: Stamatoyannopoulos AWNG, Majerus PW, Varmus H, editors. The molecular basis of blood diseases. Philadelphia: WB Saunders; 1994. p. 157–205.

    Google Scholar 

  • Wu B, Moulton HM, Iversen PL, Jiang J, Li J, Li J, Spurney CF, Sali A, Guerron AD, Najaraju K, Doran T, Lu P, Xiao X, Lu QL. Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oliogmer. Proc Natl Acad Sci U S A. 2008;105:14814–9.

    Article  CAS  Google Scholar 

  • Yin HF, Moulton HM, Betts C, Seow Y, Boutilier J, Iverson PL, Wood MJA. A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice. Hum Mol Genet. 2009;18(22):4405–14.

    Article  CAS  Google Scholar 

  • Yokota T, Lu Q, Partridge T, Kobayashi A, et al. Efficacy of systemic mopholino exon-skipping in Duchenne dystrophy dogs. Ann Neurol. 2009;65:667–76.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. LS Pharma, Oregon State University, Grand Jct, CO, USA

    Patrick L. Iversen

Authors
  1. Patrick L. Iversen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Iversen, P.L. (2018). Eteplirsen. In: Molecular Basis of Resilience. Springer, Cham. https://doi.org/10.1007/978-3-319-98164-2_11

Download citation

Publish with us

Policies and ethics

Search

Navigation