CC BY 4.0 · Synlett 2024; 35(11): 1247-1252
DOI: 10.1055/a-2211-6490
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Japan/Netherlands Gratama Workshop

Applying Lessons Learned from Developing Exon Skipping for Duchenne to Developing Individualized Exon Skipping Therapy for Patients with Neurodegenerative Diseases

Annemieke Aartsma-Rus  ∗
The author receives grant funding from the European Union, Duchenne Parent Project (Netherlands), ZonMw (Netherlands), Prinses Beatrix Spierfonds (Netherlands), Duchenne Research Fund (UK), Entrada Therapeutics, Sarepta Therapeutics, U.S. Department of Defense, Muscular Dystrophy Association (USA), and Stichting Ammodo (Netherlands).
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Abstract

Antisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by interfering with the splicing process so mutated dystrophin transcripts become readable allowing production of partially functional dystrophin proteins, rather than nonfunctional dystrophins. After over 2 decades of research, 4 ASOs are FDA approved for DMD, but clinical effects are suboptimal due to limited delivery to skeletal muscle. At the same time, ASOs for brain diseases result in much more functional impact, because local delivery allows higher exposure to the target tissue at a low dose and infrequent treatment regimen. This has opened the way to develop ASOs in an individualized setting, as was exemplified by the development of Milasen to treat a patient with CLN7 Batten disease.

In this perspective paper I will share my personal journey as one of the pioneers of ASO-mediated exon skipping development for DMD, currently applying expertise gained and lessons learned along the way to develop exon skipping ASOs for eligible patients with genetic brain diseases in a national and international setting.

1 Duchenne and Antisense-Mediated Exon Skipping

2 Opportunities for Treating Central Nervous System Diseases and Developing Individualized ASOs for Central Nervous System Diseases

3 Collaborative Spirit to Develop Individualized Treatments Globally

4 Global Implementation

5 Concluding Remarks

Key words

antisense oligonucleotide - exon skipping - N-of-1 treatment - rare disease - therapy


Publication History

Received: 01 November 2023

Accepted after revision: 09 November 2023

Accepted Manuscript online:
15 November 2023

Article published online:
19 December 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Kuijper EC, Bergsma AJ, Pijnappel W, Aartsma-Rus A. J Inherited Metab. Dis. 2021; 44: 72
    CrossrefPubMed
  • 2 Aartsma-Rus A. Hum. Gene Ther. 2023; 34: 372
    CrossrefPubMed
  • 3 Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Nat. Rev. Dis. Primers 2021; 7: 13
    CrossrefPubMed
  • 4 van Deutekom JC, Bremmer-Bout M, Janson AA, Ginjaar IB, Baas F, den Dunnen JT, van Ommen GJ. Hum. Mol. Genet. 2001; 10: 1547
    CrossrefPubMed
  • 5 Pramono ZA, Takeshima Y, Alimsardjono H, Ishii A, Takeda S, Matsuo M. Biochem. Biophys. Res. Commun. 1996; 226: 445
    CrossrefPubMed
  • 6 Mann CJ, Honeyman K, Cheng AJ, Ly T, Lloyd F, Fletcher S, Morgan JE, Partridge TA, Wilton SD. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 42
    CrossrefPubMed
  • 7 Wilton SD, Lloyd F, Carville K, Fletcher S, Honeyman K, Agrawal S, Kole R. Neuromuscular Disord. 1999; 9: 330
    CrossrefPubMed
  • 8 Dunckley MG, Manoharan M, Villiet P, Eperon IC, Dickson G. Hum. Mol. Genet. 1998; 7: 1083
    CrossrefPubMed
  • 9 Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA, Fletcher S, Partridge TA, Wilton SD. Nat. Med. 2003; 9: 1009
    CrossrefPubMed
  • 10 Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, den Dunnen JT. Hum. Mutat. 2009; 30: 293
    CrossrefPubMed
  • 11 Wilton SD, Fall AM, Harding PL, McClorey G, Coleman C, Fletcher S. Mol. Ther. 2007; 15: 1288
    CrossrefPubMed
  • 12 Heemskerk H, de Winter C, van Kuik P, Heuvelmans N, Sabatelli P, Rimessi P, Braghetta P, van Ommen GJ, de Kimpe S, Ferlini A, Aartsma-Rus A, van Deutekom JC. Mol. Ther. 2010; 18: 1210
    CrossrefPubMed
  • 13 Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC. N. Engl. J. Med. 2011; 364: 1513
    CrossrefPubMed
  • 14 Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ, Dickson G, Wood MJ, Wilton SD, Straub V, Kole R, Shrewsbury SB, Sewry C, Morgan JE, Bushby K, Muntoni F. Lancet 2011; 378: 595
    CrossrefPubMed
  • 15 Takeshima Y, Yagi M, Wada H, Ishibashi K, Nishiyama A, Kakumoto M, Sakaeda T, Saura R, Okumura K, Matsuo M. Pediatr. Res. 2006; 59: 690
    CrossrefPubMed
  • 16 Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM. Ann. Neurol. 2013; 74: 637
    CrossrefPubMed
  • 17 Hammond SM, Aartsma-Rus A, Alves S, Borgos SE, Buijsen RA. M, Collin RW. J, Covello G, Denti MA, Desviat LR, Echevarría L, Foged C, Gaina G, Garanto A, Goyenvalle AT, Guzowska M, Holodnuka I, Jones DR, Krause S, Lehto T, Montolio M, Van Roon-Mom W, Arechavala-Gomeza V. EMBO Mol. Med. 2021; 13: e13243
    CrossrefPubMed
  • 18 Rigo F, Chun SJ, Norris DA, Hung G, Lee S, Matson J, Fey RA, Gaus H, Hua Y, Grundy JS, Krainer AR, Henry SP, Bennett CF. J. Pharmacol. Exp. Ther. 2014; 350: 46
    CrossrefPubMed
  • 19 Mortberg MA, Gentile JE, Nadaf NM, Vanderburg C, Simmons S, Dubinsky D, Slamin A, Maldonado S, Petersen CL, Jones N, Kordasiewicz HB, Zhao HT, Vallabh SM, Minikel EV. Nucleic Acids Res. 2023; 51: 7109
    CrossrefPubMed
  • 20 Aartsma-Rus A. Nucleic Acid Ther. 2017; 27: 67
    CrossrefPubMed
  • 21 Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC. N. Engl. J. Med. 2017; 377: 1723
    CrossrefPubMed
    • 22a Lauffer M. 2023, in press.
    • 22b Zardetto et al., 2023, in press.
  • 23 Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW. N. Engl. J. Med. 2019; 381: 1644
    CrossrefPubMed
  • 24 Kim J, Woo S, de Gusmao CM, Zhao B, Chin DH, DiDonato RL, Nguyen MA, Nakayama T, Hu CA, Soucy A, Kuniholm A, Thornton JK, Riccardi O, Friedman DA, El Achkar CM, Dash Z, Cornelissen L, Donado C, Faour KN. W, Bush LW, Suslovitch V, Lentucci C, Park PJ, Lee EA, Patterson A, Philippakis AA, Margus B, Berde CB, Yu TW. Nature 2023; 619: 828
    CrossrefPubMed
  • 25 https://www.rnatherapy.nl
  • 26 Aartsma-Rus A. Nat. Med. 2021; 27: 939
    CrossrefPubMed
  • 27 Gleeson JG, Bennett CF, Carroll JB, Cole T, Douville J, Glass S, Tekendo-Ngongang C, Williford AC, Crooke ST. Nat. Med. 2023; 29: 1302
    CrossrefPubMed
  • 28 https://www.1mutation1medicine.eu/ (accessed Dec. 13, 2023 )
  • 29 https://www.n1collaborative.org/ (accessed Dec. 13, 2023)
  • 30 https://irdirc.org/preparing-for-genetic-n-of-1-treatments-of-patients-with-ultra-rare-mutations/ (accessed Dec. 13, 2023)
  • 31 Aartsma-Rus, A.; manuscript in preparation.
  • 32 Aartsma-Rus A, Garanto A, van Roon-Mom W, McConnell EM, Suslovitch V, Yan WX, Watts JK, Yu TW. Nucleic Acid Ther. 2023; 33: 17
    CrossrefPubMed
  • 33 Aartsma-Rus A, van Roon-Mom W, Lauffer M, Siezen C, Duijndam B, Coenen-de Roo T, Schüle R, Synofzik M, Graessner H. RNA 2023; 29: 446
    CrossrefPubMed
  • 34 Synofzik M, van Roon-Mom WM. C, Marckmann G, van Duyvenvoorde HA, Graessner H, Schüle R, Aartsma-Rus A. Nucleic Acid Ther. 2022; 32: 83
    CrossrefPubMed
  • 35 https://www.nytimes.com/2022/10/26/health/gene-treatment-epilepsy-antisense-brain.html (accessed Dec. 13, 2023)
  • 36 Becker LL, Weiß C, Tietze A, Martiny V, Kaindl AM. Neuropediatrics 2021; 52: 219
    Article in Thieme ConnectPubMed
  • 37 Tabrizi SJ, Estevez-Fraga C, van Roon-Mom WM. C, Flower MD, Scahill RI, Wild EJ, Muñoz-Sanjuan I, Sampaio C, Rosser AE, Leavitt BR. Lancet Neurol. 2022; 21: 645
    CrossrefPubMed