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Review of neurodegenerative disease and splice modulation

Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies.
Li D, McIntosh CS, Mastaglia FL, Wilton SD, Aung-Htut MT. Transl Neurodegener. 2021 May 20;10(1):16. doi: 10.1186/s40035-021-00240-7.

Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease (Review)

Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease.
El Marabti E, Abdel-Wahab O. Trends Mol Med. 2021 May 13:S1471-4914(21)00100-3. doi: 10.1016/j.molmed.2021.04.005.

SARS-CoV-2 RNA targets for steric blocking

Potantial targets for steric blocking on the SARS-CoV-2 genome and transcripts.

The SARS-CoV-2 RNA interactome.
Lee S, Lee YS, Choi Y, Son A, Park Y, Lee KM, Kim J, Kim JS, Kim VN. Mol Cell. 2021 Apr 27:S1097-2765(21)00327-0. doi: 10.1016/j.molcel.2021.04.022. Online ahead of print.

Positive control, human and mouse splice modification

Flynn LL, Mitrpant C, Adams A, Pitout IL, Stirnweiss A, Fletcher S, Wilton SD. Targeted SMN Exon Skipping: A Useful Control to Assess In Vitro and In Vivo Splice-Switching Studies. Biomedicines. 2021;9(5):552. doi:10.3390/biomedicines9050552

"To confirm oligomer delivery and antisense activity, a positive control AO sequence with well characterized target-specific effects is recommended. Here, we describe splice-switching antisense oligomer sequences targeting the ubiquitously expressed human and mouse SMN and Smn genes for use as control AOs for this purpose. We report two AO sequences that induce targeted skipping of SMN1/SMN2 exon 7 and two sequences targeting the Smn gene, that induce skipping of exon 5 and exon 7. These antisense sequences proved effective in inducing alternative splicing in both in vitro and in vivo models and are therefore broadly applicable as controls."

MO knockdown of ectopic GFP in axlotl

There are few papers reporting using a Morpholino to directly target GFP in vivo; here is one example.
Schnapp E, Tamaka EM. Quantitative evaluation of morpholino-mediated protein knockdown of GFP, MSX1, and PAX7 during tail regeneration in Ambystoma mexicanum. Dev Dyn. 2005 Jan;232(1):162-70.

Oligo types, therapeutic Morpholinos, upregulation with Morpholinos

Here are some types of oligos sorted by their mechanisms.

RNase-H dependent

  • DNA
  • Phosphorothioate DNA

RNase-independent (steric blocking oligos)

  • Morpholinos
  • 2’-O-substituted oligos (often phosphorothioate linkages)
    • 2’-O methyl
    • 2’-O methoxyethyl
  • PNA (peptide nucleic acids)
  • LNA (locked nucleic acid)

Argonaute dependent

  • siRNA
  • shRNA

About the Morpholino drugs

The mechanism of the Morpholino drugs for Duchenne muscular dystrophy (DMD) is to induce skipping of an exon so that the downstream sequence is frameshifted. These are used to treat specific frameshift mutations of the human dystrophin gene, so that the frameshift induced by the oligo restores the correct reading frame to make the dystrophin protein. Frameshift mutations are either insertions or deletions in the DNA or splice-site mutations that cause insertions or deletions in the RNA. Typically these drugs have been used in the clinic to treat deletions, but research is ongoing to use oligos for treatment of insertions. The wild-type dystrophin has a reading frame that makes a functional protein, the mutation causes a frameshift so everything after the mutation has altered amino acid sequence, the oligo restores the reading frame so that the protein is made with a missing part somewhere in the middle but the downstream part of the protein has the same amino acid sequence as the protein made from the wild-type gene.

These are the Morpholino drugs currently US FDA approved for DMD (April 2021):

- Sarepta Therapeutics

eteplirsen EXONDYS 51 (SRP-4051) exon 51 dystrophin
golodirsen VYONDYS 53 (SRP-4053) exon 53 dystrophin
casimersen AMONDYS 45 (SRP-4045) exon 45 dystrophin

- NS Pharma (Nippon Shinyaku)

viltolarsen (NS-065/ NCNP-01) exon 53 dystrophin

There is an interesting oligo currently in clinical trials from Sarepta Therapeutics. This is SRPT-5051, which is a Morpholino with the same target as eteplirsen but with a cell-penetrating peptide attached.

Blocking mutant splice sites

Instead of using a splice-modifying oligo to correct a reading frame, there is a different approach available for treating some mutations. Occasionally a mutation will create a new splice site. This can redirect splicing from the one of the splice sites used in the wild-type pre-mRNA to a new location in an exon or an intron. An early example of using an RNase-independent oligo to block a splicing site was the work by Ryszard Kole’s group with mutations causing beta-thalassemia, which is caused by defects in the human beta-globin gene ( They worked with splice sites created by mutations and showed that by blocking the mutant splice site, splicing could be redirected to the wild-type splice site. Soon their early work with 2’-O-methyl phosphorothioate oligos was supplanted by Morpholino oligos and after a handful more papers Kole joined Sarepta Therapeutics (then called AVI BioPharma) where he participated in development of the DMD Morpholinos.

Another disease where research has been done with oligos blocking mutant splice sites to restore normal splicing is cystic fibrosis, caused by mutations in the CFTR gene. Morpholinos have been used for blocking mutant CFTR splice sites (for example,

Upregulation with Morpholino oligos

Usually researchers think of antisense, and Morpholinos, as knockdown reagents. However, both of the treatments for mutations that I have described, reading-frame correction and blocking new splice sites created by mutations, are upregulation strategies that restore some or all of the function of a lost protein. A strategy we’ve not yet discussed can be used when an mRNA undergoes several splicing pathways, one leading to a functional protein and other(s) leading to splice forms with premature termination codons and undergoing nonsense-mediated decay (NMD); in some cases a Morpholino can be designed to shift the splicing away from the NMD mRNA to form more of the useful mRNA that makes a functional protein. Another upregulation strategy is to block the microRNA response element on the 3’-UTR of an mRNA, relieving that mRNA of translation suppression by an miRNA. Still another is offered when an intronic polyadenylation signal competes with splicing, so that full length mRNA is produced and truncated mRNA with an early poly-A tail is also produced; in this case, blocking the polyadenylation sequence with a Morpholino caused more of the full-length RNA to be made (

Other approaches: splice regulation

Many splice-modifying Morpholino are targeted to the intronic side of splice junctions in order to block snRNP binding. There are other useful targets for splice-modification though; The DMD drug eteplirsen targets within an exon to block the binding site of an exonic splice enhancer, flipping a regulatory switch that causes exclusion of exon 51 from the mature dystrophin mRNA. The binding sites for splice regulatory proteins, such as exonic splice enhancers, intronic splice suppressors, etc. are also good Morpholino targets but can be more difficult to find; so far, most researchers have used splice junction oligos with a few researchers and some pharmaceutical development companies exploring the splice-regulatory targets.

Papers describing Morpholinos used in DMD studies

Papers describing Morpholinos used in DMD studies
Note: this is not an exhaustive list. Using DMD-related keywords in the Morpholino publications database will turn up many more citations. Some key papers are marked with triple astrisks (***). The papers are divided into non-clinical (first) and clinical (following).


Maruyama R, Yokota T. Antisense Oligonucleotide Treatment in a Humanized Mouse Model of Duchenne Muscular Dystrophy and Highly Sensitive Detection of Dystrophin Using Western Blotting. Methods Mol Biol. 2021;2224:203-214. doi: 10.1007/978-1-0716-1008-4_15.

Lim KRQ, Huang Y, Maruyama R, Woo S, Dzierlega K, Moulton H, Yokota T. Development of a Minimized Exons 45-55 Skipping Cocktail for the Treatment of Duchenne Muscular Dystrophy. Molec Ther. 2020;28(4S1):113 abstract 237. doi:10.1016/j.ymthe.2020.04.019.

Takizawa H, Hara Y, Mizobe Y, Ohno T, Suzuki S, Inoue K, Takeshita E, Shimizu-Motohashi Y, Ishiyama A, Hoshino M, Komaki H, Takeda S, Aoki Y. Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride. Sci Rep. 2019;9(1):3807. doi:10.1038/s41598-019-40421-z.

Lim KRQ, Echigoya Y, Nagata T, Kuraoka M, Kobayashi M, Aoki Y, Partridge T, Maruyama R, Takeda S, Yokota T. Efficacy of multi-exon skipping treatment in Duchenne muscular dystrophy dog model neonates. Molec Therapy. 2018;[Epub ahead of print] doi:10.1016/j.ymthe.2018.10.011.

Akpulat U, Wang H, Becker K, Contreras A, Partridge T, Novak J, Cirak S. Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides may increase Exon Skipping Efficacy in Duchenne Muscular Dystrophy. Molec Ther Nucleic Acids. 2018;[Epub ahead of print] doi:10.1016/j.omtn.2018.10.002.

Blain AM, Greally E, McClorey G, Manzano R, Betts CA, Godfrey C, O'Donovan L, Coursindel T, Gait MJ, Wood MJ, MacGowan GA, Straub VW. Peptide-conjugated phosphodiamidate oligomer-mediated exon skipping has benefits for cardiac function in mdx and Cmah-/-mdx mouse models of Duchenne muscular dystrophy. PLoS One. 2018 Jun 18;13(6):e0198897. doi: 10.1371/journal.pone.0198897. eCollection 2018.

Veltrop M, van Vliet L, Hulsker M, Claassens J, Brouwers C, Breukel C, van der Kaa J, Linssen MM, den Dunnen JT, Verbeek S, Aartsma-Rus A, van Putten M. A dystrophic Duchenne mouse model for testing human antisense oligonucleotides. PLoS ONE. 2018;13(2):e0193289. doi:10.1371/journal.pone.0193289.

Negishi Y, Ishii Y, Nirasawa K, Sasaki E, Endo-Takahashi Y, Suzuki R, Maruyama K. PMO Delivery System Using Bubble Liposomes and Ultrasound Exposure for Duchenne Muscular Dystrophy Treatment. Methods Mol Biol. 2018;1687:185-192. doi: 10.1007/978-1-4939-7374-3_13.

Miyatake S, Mizobe Y, Takizawa H, Hara Y, Yokota T, Takeda S, Aoki Y. Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy. Methods Mol Biol. 2018;1687:123-141. doi: 10.1007/978-1-4939-7374-3_9.

Novak JS, Hogarth MW, Boehler JF, Nearing M, Vila MC, Heredia R, Fiorillo AA, Zhang A, Hathout Y, Hoffman EP, Jaiswal JK, Nagaraju K, Cirak S, Partridge TA. Myoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle. Nat Commun. 2017 Oct 16;8(1):941. doi: 10.1038/s41467-017-00924-7.

Echigoya Y, Rowel Q. Lim KRQ, Trieu N, Bao B, Miskew B, Vila MC, Novak JS, Hara Y, Lee J, Touznik A, Mamchaoui K, Aoki Y, Takeda S, Nagaraju K, Mouly V, Maruyama R, Duddy W, Yokota T. Quantitative antisense screening and optimization for exon 51 skipping in Duchenne muscular dystrophy. Molec Ther. 2017:[Accepted manucsript] doi:10.1016/j.ymthe.2017.07.014.

*** Echigoya Y, Nakamura A, Nagata T, Urasawa N, Lim KR, Trieu N, Panesar D, Kuraoka M, Moulton HM, Saito T, Aoki Y, Iversen P, Sazani P, Kole R, Maruyama R, Partridge T, Takeda S, Yokota T. Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2017 Apr 3. pii: 201613203. doi: 10.1073/pnas.1613203114. [Epub ahead of print].

Maruyama R, Echigoya Y, Caluseriu O, Aoki Y, Takeda S, Yokota T. Systemic Delivery of Morpholinos to Skip Multiple Exons in a Dog Model of Duchenne Muscular Dystrophy. Methods Mol Biol. 2017;1565:201-213. doi: 10.1007/978-1-4939-6817-6_17.

*** Miskew Nichols B, Aoki Y, Kuraoka M, Lee JJ, Takeda S, Yokota T. Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy. J Vis Exp. 2016 May 24;(111). doi: 10.3791/53776.

Boisguerin P, O'Donovan L, Gait MJ, Lebleu B. In Vitro Assays to Assess Exon Skipping in Duchenne Muscular Dystrophy. Methods Mol Biol. 2015;1324:317-29. doi: 10.1007/978-1-4939-2806-4_20.

Echigoya Y, Mouly V, Garcia L, Yokota T, Duddy W. In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in duchenne muscular dystrophy. PLoS One. 2015 Mar 27;10(3):e0120058. doi: 10.1371/journal.pone.0120058. eCollection 2015.

Shabanpoor F, McClorey G, Saleh AF, Järver P, Wood MJA, Gait MJ. Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy. Nucl Acids Res. 2015 Jan;43(1):29-39. doi: 10.1093/nar/gku1256. Epub 2014 Dec 2.

Takeda S. Exon skipping approach to duchenne muscular dystrophy. Rinsho Shinkeigaku. 2014;54(12):1071-3. doi: 10.5692/clinicalneurol.54.1071.

Cao L, Han G, Gu B, Yin H. Wild-type mouse models to screen antisense oligonucleotides for exon-skipping efficacy in duchenne muscular dystrophy. PLoS One. 2014 Nov 3;9(11):e111079. doi: 10.1371/journal.pone.0111079. eCollection 2014.

Johnson NM, Farr GH, Maves L. The HDAC Inhibitor TSA Ameliorates a Zebrafish Model of Duchenne Muscular Dystrophy. PLOS Currents Muscular Dystrophy. 2013 Sep 17. Edition 1. doi:10.1371/

Betts CA, Wood MJ. Cell Penetrating Peptide Delivery of Splice Directing Oligonucleotides as a Treatment for Duchenne Muscular Dystrophy. Curr Pharm Des. 2012 Nov 2. [Epub ahead of print].

Malerba A, Kang JK, McClorey G, Saleh AF, Popplewell L, Gait MJ, Wood MJA, Dickson G. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy. Mol Ther Nucleic Acids. 2012;1:e62. doi:/10.1038/mtna.2012.54.

*** Yokota T, Nakamura A, Nagata T, Saito T, Kobayashi M, Aoki Y, Echigoya Y, Partridge T, Hoffman EP, Takeda S. Extensive and Prolonged Restoration of Dystrophin Expression with Vivo-Morpholino-Mediated Multiple Exon Skipping in Dystrophic Dogs. Nucleic Acid Ther. 2012 Oct;22(5):306-15. doi: 10.1089/nat.2012.0368. Epub 2012 Aug 13.

Aoki Y, Yokota T, Nagata T, Nakamura A, Tanihata J, Saito T, Duguez SMR, Nagaraju K, Hoffman EP, Partridge T, Takeda S. Bodywide skipping of exons 45–55 in dystrophic mdx52 mice by systemic antisense delivery. PNAS. 2012;[Epub ahead of print] doi:10.1073/pnas.1204638109.

Kole R, Leppert BJ. Targeting mRNA Splicing as a Potential Treatment for Duchenne Muscular Dystrophy. Discov Med. 2012;14(74):59-69.

Kendall GC, Mokhonova EI, Moran M, Sejbuk NE, Wang DW, Silva O, Wang RT, Martinez L, Lu QL, Damoiseaux R, Spencer MJ, Nelson SF, Miceli MC. Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy. Sci Transl Med. 2012 4:164ra160. doi:10.1126/scitranslmed.3005054 .

*** Yokota T, Hoffman E, Takeda S. Antisense oligo-mediated multiple exon skipping in a dog model of duchenne muscular dystrophy. Methods Mol Biol. 2011;709:299-312.

*** Kawahara G, Karpf JA, Myers JA, Alexander MS, Guyon JR, Kunkel LM. Drug screening in a zebrafish model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5331-6. Epub 2011 Mar 14.

Yokota T, Hoffman E, Takeda S. Antisense oligo-mediated multiple exon skipping in a dog model of duchenne muscular dystrophy. Methods Mol Biol. 2011;709:299-312.

Yin H, Moulton H, Betts C, Wood M. CPP-Directed Oligonucleotide Exon Skipping in Animal Models of Duchenne Muscular Dystrophy. Methods Mol Biol. 2011;683:321-38.

Wilton SD, Fletcher S. Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents. The Application of Clinical Genetics. 2011 Mar 11;2011(4):29-44.

*** 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. 2011 May 3. [Epub ahead of print].

*** Berger J, Berger S, Jacoby AS, Wilton SD, Currie PD. Evaluation of Exon-Skipping Strategies for Duchenne Muscular Dystrophy Utilizing Dystrophin-deficient Zebrafish. J Cell Mol Med. 2011 Jan 20. doi: 10.1111/j.1582-4934.2011.01260.x. [Epub ahead of print].

*** Aoki Y, Nakamura A, Yokota T, Saito T, Okazawa H, Nagata T, Takeda S. In-frame Dystrophin Following Exon 51-Skipping Improves Muscle Pathology and Function in the Exon 52-Deficient mdx Mouse. Mol Ther. 2010 Sep 7. [Epub ahead of print].

Partridge T. The Potential of Exon Skipping for Treatment for Duchenne Muscular Dystrophy. J Child Neurol. 2010 Jun 2. [Epub ahead of print].

Wang Q, Yin H, Camelliti P, Betts C, Moulton H, Lee H, Saleh AF, Gait MJ, Wood MJ. In vitro evaluation of novel antisense oligonucleotides is predictive of in vivo exon skipping activity for Duchenne muscular dystrophy. J Gene Med. 2010 Mar 16. [Epub ahead of print].

*** Moulton HM, Moulton JD. Morpholinos and Their Peptide Conjugates: Therapeutic Promise and Challenge for Duchenne Muscular Dystrophy. Biochim Biophys Acta. 2010;1798(12):2296-2303.

Moulton HM, Wu B, Jearawiriyapaisarn N, Sazani P, Lu QL, Kole R. Peptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy. Ann N Y Acad Sci. 2009 Sep;1175:55-60.

Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E. Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs. Ann Neurol. 2009 Jun;65(6):667-76. doi: 10.1002/ana.21627.

*** Mitrpant C, Fletcher S, Wilton SD. Personalised Genetic Intervention for Duchenne Muscular Dystrophy: Antisense Oligomers and Exon Skipping. Curr Mol Pharmacol. 2009 Jan;2(1):110-121.

Heemskerk HA, de Winter CL, de Kimpe SJ, van Kuik-Romeijn P, Heuvelmans N, Platenburg GJ, van Ommen GJ, van Deutekom JC, Aartsma-Rus A. In vivo comparison of 2'-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping. J Gene Med. 2009 Jan 12. [Epub ahead of print].

*** Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E. Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs. Ann Neurol. 2009 Jun;65(6):667-76. doi: 10.1002/ana.21627.

Yokota T, Duddy W, Partridge T. Optimizing exon skipping therapies for DMD. Acta Myol. 2007 Dec;26(3):179-84.

Yokota T, Pistilli E, Duddy W, Nagaraju K. Potential of oligonucleotide-mediated exon-skipping therapy for Duchenne muscular dystrophy. Expert Opin Biol Ther. 2007 Jun;7(6):831-842.



*** Scaglioni D, Catapano F, Ellis M, Torelli S, Chambers D, Feng L, Beck M, Sewry C, Monforte M, Harriman S, Koenig E, Malhotra J, Popplewell L, Guglieri M, Straub V, Mercuri E, Servais L, Phadke R, Morgan J, Muntoni F. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun. 2021 Jan 6;9(1):7. doi: 10.1186/s40478-020-01106-1.

Komaki H, Takeshima Y, Matsumura T, Ozasa S, Funato M, Takeshita E, Iwata Y, Yajima H, Egawa Y, Toramoto T, Tajima M, Takeda S. Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study. Ann Clin Transl Neurol. 2020 Dec 7. doi: 10.1002/acn3.51235. Online ahead of print.

*** Clemens PR, Rao VK, Connolly AM, Harper AD, Mah JK, Smith EC, McDonald CM, Zaidman CM, Morgenroth LP, Osaki H, Satou Y, Yamashita T, Hoffman EP, for the CINRG DNHS Investigators. Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping. JAMA Neurology. 2020;[Epub] doi:10.1001/jamaneurol.2020.1264.

Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, Charleston JS, Sardone V, Domingos J, Dickson G, Straub V, Guglieri M, Mercuri E, Servais L, Muntoni F; SKIP-NMD Study Group. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020 Mar 5. pii: 10.1212/WNL.0000000000009233. doi: 10.1212/WNL.0000000000009233. [Epub ahead of print].

*** Alfano LN, Charleston JS, Connolly AM, Cripe L, Donoghue C, Dracker R, Dworzak J, Eliopoulos H, Frank DE, Lewis S, Lucas K, Lynch J, Milici AJ, Flynt A, Naughton E, Rodino-Klapac LR, Sahenk Z, Schnell FJ, Young GD, Mendell JR, Lowes LP. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore). 2019 Jun;98(26):e15858. doi: 10.1097/MD.0000000000015858.

Watanabe N, Nagata T, Satou Y, Masuda S, Saito T, Kitagawa H, Komaki H, Takagaki K, Takeda S. NS-065/NCNP-01: An Antisense Oligonucleotide for Potential Treatment of Exon 53 Skipping in Duchenne Muscular Dystrophy. Mol Ther Nucleic Acids. 2018 Sep 27;13:442-449. doi: 10.1016/j.omtn.2018.09.017. [Epub ahead of print].

Komaki H, Takeshima Y, Matsumura T, Ozasa S, Funato M, Egawa Y, Takeda S. A Japanese phase I/II study of NS-065/NCNP-01, exon 53 skipping drug, in patients with Duchenne muscular dystrophy - a dose-finding study. Neuromusc Disord. 2018;28:P129. doi:10.1016/j.nmd.2018.06.157.Komaki H, Takeshima Y, Matsumura T, Ozasa S, Funato M, Egawa Y, Takeda S. A Japanese phase I/II study of NS-065/NCNP-01, exon 53 skipping drug, in patients with Duchenne muscular dystrophy - a dose-finding study. Neuromusc Disord. 2018;28:P129. doi:10.1016/j.nmd.2018.06.157.

Clemens P, Rao V, Connolly A, Harper A, Mah J, Smith E, McDonald C, Morgenroth L, Osaki H, Hoffman E. A phase II, dose finding study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy. Neuromusc Disord. 2018;28(Suppl 2):S67-S68. doi:10.1016/j.nmd.2018.06.156

*** Charleston JS, Schnell FJ, Dworzak J, Donoghue C, Lewis S, Chen L, Young GD, Milici AJ, Voss J, DeAlwis U, Wentworth B, Rodino-Klapac LR, Sahenk Z, Frank D, Mendell JR. Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. Neurology. 2018 May 11. pii: 10.1212/WNL.0000000000005680. doi: 10.1212/WNL.0000000000005680. [Epub ahead of print].

Khan N, Han L, Kinane B, Gordish-Dressman H, Lowes L, McDonald C. Eteplirsen treatment attenuates respiratory decline in ambulatory and non-ambulatory patients with Duchenne muscular dystrophy. Neuromusc Disord. 2018;28:P125. doi:10.1016/j.nmd.2018.06.153.

Komaki H, Nagata T, Saito T, Masuda S, Takeshita E, Sasaki M, Tachimori H, Nakamura H, Aoki Y, Takeda S. Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci Transl Med. 2018 Apr 18;10(437). pii: eaan0713. doi: 10.1126/scitranslmed.aan0713.

*** Kinane TB, Mayer OH, Duda PW, Lowes LP, Moody SL, Mendell JR. Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. J Neuromusc Dis. 2017;[Epub ahead of print] doi:10.3233/JND-170272.

Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. doi: 10.1002/ana.24555. Epub 2016 Jan 8.

*** Komaki H, Nagata T, Saito T, Masuda S, Takeshita E, Tachimori H, Sasaki M, Takeda S. Exon 53 skipping of the dystrophin gene in patients with Duchenne muscular dystrophy by systemic administration of NS-065/NCNP-01: A phase 1, dose escalation, first-in-human study. Neuromusc Disord. 2015;26(2)S261-2 doi:10.1016/j.nmd.2015.06.276.

No Authors Listed. A Phase I/IIa Clinical Trial in Duchenne Muscular Dystrophy Using Systemically Delivered Morpholino Antisense Oligomer to Skip Exon 53 (SKIP-NMD). Human Gene Therapy Clinical Development. June 2015, 26(2): 92-95. doi:10.1089/humc.2015.2528.

Mendell JR, Rodino-Klapac L, Sahenk Z, Rouch K, Bird L, Lowes L, Alfano L, Berry K, Lewis S, Shontz K, Flanigan K, Shilling C, Duda P, Saoud J. Eteplirsen, a Phosphorodiamidate Morpholino Oligomer (PMO) for the Treatment of Duchenne Muscular Dystrophy (DMD): 168 Week Update on Six-Minute Walk Test (6MWT), Pulmonary Function Testing (PFT), and Safety. European Journal of Paediatric Neurology. 2015;19(Supp 1):S69

Mendell JR, Rodino-Klapac L, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Malik V, Shontz K, Flanigan KM, Shilling C, Sazani P, Saoud J, Duda P, Kaye E. G.O.24: Eteplirsen in Duchenne Muscular Dystrophy (DMD): 3year update on Six-Minute Walk Test (6MWT) and Safety. Neuromusc Disord. 2014;24(9):922. doi:10.1016/j.nmd.2014.06.423.

*** Sazani P, Magee T, Charleston JS, Shanks C, Zhang J, Carver M, Rodino-Klapac L, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Malik V, Shontz K, Flanigan K, Shilling C, Bhalli J, Kaur H, Walisser J, Forget J, Saoud J, Mendell JR, Kaye E . Safety and pharmacokinetic profile of eteplirsen, SRP-4045, and SRP-4053, three phosphorodiamidate morpholino oligomers (PMOs) for the treatment of patients with Duchenne muscular dystrophy (DMD). Neuromusc Dis. 2014. 24(9-10):828. doi:10.1016/j.nmd.2014.06.124.

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A description of using Morpholinos to block splice-regulatory protein binding sites

Biayna J, Mazuelas H, Gel B, Terribas E, Dumbovic G, Rosas I, Fernández-Rodriguez J, Blanco I, Castellanos E, Carrió M, Lazaro C, Serra E. Using antisense oligonucleotides for the physiological modulation of the alternative splicing of NF1 exon 23a during PC12 neuronal differentiation. Sci Rep. 2021;11(1):3661. doi:10.1038/s41598-021-83152-w


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