RNA Intereference – Clinical
Applications
Applications and Clinical Perspectives
• Inherent difficulties with blocking many desirable targets using conventional approaches have prompted many researchers to
consider using RNAi as a therapeutic approach (Pecot et al. 2011).
• Three years after Fire and Mello’s discovery of RNA interference (Fire et al. 1998), it was demonstrated that siRNA could achieve sequence-specific knockdown in a mammalian cell line.
• Shortly thereafter, the first successful use of synthetic siRNA was achieved by targeting a sequence from hepatitis-C virus in mice (McCaffrey et al. 2002).
• The clinical applications appear endless: any gene whose overexpression contributes to disease is a potential
target, from viral genes to oncogenes, or genes
responsible for heart disease, Alzheimer’s disease, diabetes and more (Kurreck 2009; Robinson 2004).
• Numerous research groups and biotechnology companies have invested a lot of effort to develop siRNA therapeutics in various human diseases, including hereditary and
infectious diseases, as well as cancer (Chen and Zhaori
2011; Leung and Whittaker 2005; Petrocca and Lieberman 2011; Whitehead et al. 2009).
Clinical Trials
• The first siRNA based clinical study was started at the end of 2004, targeting VEGF. Inhibition of VEGF expression was expected to block neovascularization in patients with AMD (Kurreck 2009). This siRNA was tested under the name Bevasiranib in a Phase III trial by the company OPKO Health. However it was terminated in 2009 before reaching the end of the study since Independent Data Monitoring Committee review suggested that the trial, as designed, was unlikely to meet its primary endpoint (http://www.opko.com/research/?
doc=ophthalmics).
• Other than AMD, other ongoing clinical trials have been focusing on acute kidney injury, asthma, hypercholesterolemia (Vaishnaw et al.
2010).
Examples
• A lot of promise has also been placed on siRNA mediated cancer therapeutics (Kurreck 2009).
• As cancer progresses, several major pathways are altered including the receptor protein tyrosine kinase, adenomatous polyposis coli, glioma-
associated oncogene, phosphoinositide 3-kinase, SMAD, hypoxia-inducible transcription factor, pRb, p53 and apoptosis pathways.
• Many genes which are upregulated in these pathways have been targeted by siRNA (Pai et al. 2005).
• There are many published in vivo studies showing that tumour growth can be inhibited or slowed down in animal models when siRNA against CD31, bcl-2 or K-ras were used (Kurreck 2009; Leung and Whittaker 2005).
• In a first clinical RNAi cancer trial, Glioblastoma
multiforme patients with untreatable brain tumours were treated. siRNAs directed against Tenascin-C was successful in preventing the re-emergence of operatively removed
glioblastomas in many patients (Zukiel et al. 2006).
• There are many other ongoing clinical trials (mainly Phase I) employing RNAi technology for cancer therapy (Table 3) and this holds a promise in the search for novel cancer
therapies.
