Biomedical Engineering Reference
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cholesterol and triglycerides. In preclinical studies, rodents with diet-induced
hypercholesterolemia that received a single administration of ApoB SNALP saw
elevated blood cholesterol levels fall to normal. Compared to other molecular
approaches in development, such as antisense, ApoB SNALP appears to have sig-
nificant advantages including markedly improved drug activity. Tekmira conducted
a phase I human clinical trial for TKM-ApoB in 2009 to evaluate the safety, toler-
ability and pharmacokinetics of escalating single doses of TKM-ApoB in patients
with elevated LDL cholesterol. The trial was also designed to provide preliminary
data on the ability of TKM-ApoB to lower serum LDL cholesterol levels. In 2011,
Tekmira was in the process of selecting a new siRNA payload and evaluating new
formulations for TKM-ApoB. Subsequent clinical studies will evaluate the safety
and efficacy of ApoB SNALP as a single agent and in combination with other
cholesterol-lowering drugs.
microRNA and the Cardiovascular System
microRNAs (miRNAs), small and mostly non-coding RNA gene products, are
molecules derived from larger segments of “precursor” RNA that are found in all
diverse multicellular organisms. miRNAs are 21-25 nucleotide transcripts that
repress gene function through interactions with target mRNAs The biological
importance of miRNAs has been investigated in cardiovascular physiology and
pathology. miRNAs expression is tightly controlled in a tissue-specific and devel-
opmental stage-specific manner and some of them are highly and specifically
expressed in cardiovascular tissues. One study has shown that at least 87 miRNAs
are altered in heart disease and that different types of heart disease are associated
with distinct changes in miRNA expression (Ikeda et al.
2007
). These data will
guide further studies of the contribution of miRNAs to pathogenesis of heart dis-
ease and therapeutics based on this knowledge.
Role of miRNAs in Angiogenesis
Embryonic lethality observed in Dicer knockout mice has been attributed to defec-
tive blood vessel formation and maintenance. These anatomical defects were
associated with altered expression of VEGF, its receptors KDR (VEGFR2) and
FLT-1 (VEGFR1), and the angiopoietin receptor, Tie-1 suggesting that miRNAs
may regulate the expression levels of crucial angiogenic factors. Screening analy-
sis of 168 human miRNAs revealed that members of the let-7 family including
miR-21, miR-126, miR-221, and miR-222 are highly expressed in endothelial
cells; thrombospondin-1, an endogenous angiogenesis inhibitor, was predicted to
be a major target for the let-7 cluster (Kuehbacher et al.
2007
). Deciphering the
miRNA network responsible for the fine-tuning of the angiogenic process might
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