title: Modulation of RNA splicing as a potential treatment for cancer.
abstract: Close to 90% of human genes are transcribed into pre-mRNA that undergoes alternative splicing, producing multiple mRNAs and proteins from single genes. This process is largely responsible for human proteome diversity, and about half of genetic disease-causing mutations affect splicing. Splice-switching oligonucleotides (SSOs) comprise an emerging class of antisense therapeutics that modify gene expression by directing pre-mRNA splice site usage. Bauman et al. investigated an SSO that up-regulated the expression of an anti-cancer splice variant while simultaneously eliminating an over-expressed cancer-causing splice variant.  This was accomplished by targeting pre-mRNA of the apoptotic regulator Bcl-x, which is alternatively spliced to express anti- and pro-apoptotic splice variants Bcl-xL and Bcl-xS, respectively. High expression of Bcl-xL is a hallmark of many cancers and is considered a general mechanism used by cancer cells to evade apoptosis. Redirection of Bcl-x pre-mRNA splicing from Bcl-xL to -xS by SSO induced apoptotic and chemosensitizing effects in various cancer cell lines. Importantly, the paper shows that delivery of Bcl-x SSO using a lipid nanoparticle redirected Bcl-x splicing and reduced tumor burden in melanoma lung metastases. This was the first demonstration of SSO efficacy in tumors in vivo. SSOs are not limited to be solely potential anti-cancer drugs. SSOs were first applied to repair aberrant splicing in thalassemia, a genetic disease, they have been used to create novel proteins (e.g., ∆7TNFR1), and they have recently progressed to clinical trials for patients with Duchenne muscular dystrophy.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA. bau@email.unc.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Bauman
authors.forename: Ryszard
authors.initials: R
authors.lastname: Kole
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D017209:Apoptosis; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D012333:RNA, Messenger