Development of therapeutic splice-switching oligonucleotides.
Synthetic splice-switching oligonucleotides (SSOs) target nuclear pre-mRNA molecules to change exon splicing and generate an alternative protein isoform. Clinical trials with two competitive SSO drugs are underway to treat Duchenne muscular dystrophy (DMD). Beyond DMD, many additional therapeutic applications are possible, with some in phase 1 clinical trials or advanced preclinical evaluation. Here, we present an overview of the central factors involved in developing therapeutic SSOs for the treatment of diseases. The selection of susceptible pre-mRNA target sequences, as well as the design and chemical modification of SSOs to increase SSO stability and effectiveness, are key initial considerations. Identification of effective SSO target sequences is still largely empirical and published guidelines are not a universal guarantee for success. Specifically, exon-targeted SSOs, which are successful in modifying dystrophin splicing, can be ineffective for splice-switching in other contexts. Chemical modifications, importantly, are associated with certain characteristic toxicities, which need to be addressed as target diseases require chronic treatment with SSOs. Moreover, SSO delivery in adequate quantities to the nucleus of target cells without toxicity can prove difficult. Last, the means by which these SSOs are administered needs to be acceptable to the patient. Engineering an efficient therapeutic SSO, therefore, necessarily entails a compromise between desirable qualities and effectiveness. Here, we describe how the application of optimal solutions may differ from case to case.
1 Institute for Liver and Digestive Health, Division of Medicine, University College London , London, NW3 2PF, United Kingdom .
Petra
P
Disterer
Adrianna
A
Kryczka
Yuqi
Y
Liu
Yusef E
YE
Badi
Jessie J
JJ
Wong
James S
JS
Owen
Bernard
B
Khoo
D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005091:Exons; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009841:Oligonucleotides / Q000235:genetics / Q000627:therapeutic use*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism
C484258:DMD protein, human; D016189:Dystrophin; D009841:Oligonucleotides; D012322:RNA Precursors