Biomedical Engineering Reference
In-Depth Information
potential for the treatment of cancer and macular degeneration by inhibiting
oncogene or angiogenic growth factor overexpression, respectively. The
scientific community's commitment to RNAi technology was evidenced by
the 2006 Nobel Prize in Medicine and by high-profile startup biotech
companies as well as billion-dollar investments from established pharmaceut-
ical companies.
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Only 10 years after the discovery of the RNAi mechanism, some siRNA
candidate drugs have entered clinical trials.
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Most siRNAs in clinical trials are
administered by local delivery such as the intravitreal or intranasal routes.
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Opko Health produced the first siRNA therapeutic (Bevasiranib) to reach a
Phase III clinical trial for the treatment of wet neovascular age-related macular
degeneration (AMD). Bevasiranib is a 21 nt-long siRNA with two
deoxythymidine (dTs) on both 39-ends and targets VEGFA mRNA.
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Although the Phase I and II trials demonstrated the safety, tolerability, and
efficacy of the siRNA, Opko terminated the Phase III study in March 2009,
based on the recommendation of the Independent Data Monitoring
Committee. The committee reasoned that the siRNA drug was unlikely to
achieve its primary endpoint of reducing vision loss in the AMD patients.
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Sirna Therapeutics developed the drug AGN-745 (formerly known as Sirna-
027), a chemically modified siRNA targeting VEGF receptor 1. As the second
RNAi drug to reach clinical trials, early data were promising, considering its
efficacy and safety in a relevant subset of patients. However, the trial was
terminated in May 2009, due to the lack of improvement in visual acuity.
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For systemic drug administration by intravenous injection, most clinically
tested siRNA therapeutics require synthetic carriers for the payload. Tekmira
has been advancing internal RNA interference (RNAi) product candidates
using the stable nucleic acid lipid particle (SNALP) carrier. TKM-ApoB was
developed for the treatment of hypercholesterolemia by a siRNA designed to
silence ApoB. In preclinical models, TKM-ApoB was delivered with high
efficiency into hepatocytes producing ApoB, where the siRNA acts to knock
down the precursor mRNA coding for the ApoB protein. The decrease in
circulating very low-density lipoproteins (VLDLs) and low-density lipopro-
teins (LDLs) resulted in significant reductions in LDLs and triglycerides.
Tekmira initiated a Phase 1 human clinical trial for TKM-ApoB in July 2009
but terminated it in January 2010. Seventeen subjects received a single dose of
TKM-ApoB at one of seven different dosing levels and six subjects received a
placebo. Of the two subjects treated at the highest dose level, one subject
experienced flu-like symptoms consistent with stimulation of the immune
system caused by the ApoB siRNA payload (http://www.tekmirapharm.com/
Programs/Products.asp). Calando Pharmaceuticals has developed a siRNA
therapeutic (CALAA-01), which is a cyclodextrin-based polymeric nanopar-
ticle containing a siRNA that targets the M2 subunit of ribonucleotide
reductase (RRM2). The nanoparticle was decorated with the human
transferrin (TF) protein and poly(ethylene glycol) (PEG) for stability.
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Given the recent successful investigational new drug (IND) filing from the U.S.
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