Biomedical Engineering Reference
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Reduced doses revealed that C12-200 inhibited F7 expression by
50% at a dose of 0.01 mg/kg, increasing efficiency by two orders or
magnitude compared to 98N
5
formulations.
This 100-fold improvement in efficiency was associated with
decreased toxicity. Liver enzymes, which are known to be elevated
in response to toxicity, remained unaffected, even at a dose of
1 mg/kg. Since drugs are often characterized by the ratio of toxic dose
to therapeutic dose (termed the therapeutic window), effective
silencing at doses several hundred-fold lower than those generating
liver toxicity suggests that this new lead compound, C12-200,
might be a clinical candidate. After efficient silencing was achieved
in mice, the authors examined hepatocyte silencing in non-human
primates. Transthyretin (TTR) was chosen as a target gene, since
mutated forms cause familial cardiomyopathy and neuropathy and
can be treated only by liver transplant.
-5 and SNALP
12
21
C12-200 reduced mRNA
expression by 90%, 85%, and 75% after doses of 0.3, 0.1, and
0.03 mg/kg, respectively.
C12-200's sizable therapeutic window also enables several
genes to be silenced concurrently. The potential to silence many
genes at once is one of the most salient advantages siRNA has
over traditional small therapeutics. Most pathologies are driven
by an assortment of genes acting in concert.
14
For example, viral
infections like Hepatitis C evade therapies by rapidly changing
gene expression.
Similarly, multiple mutations in hepatocellular
carcinoma and other cancers are responsible for aggressive growth,
metastasis, and drug resistance.
22
23
Since a single delivery vehicle
can transport all of the therapeutic RNAs together, each treated cell
would receive an integrated effect. In contrast, small molecule drugs
have different pharmacokinetic properties, so some cells might
experience the effects of one drug but not another. Accordingly, the
authors investigated whether they could silence five hepatic genes
related to cholesterol homeostasis. C12-200 was formulated with
equal amounts of siRNAs targeting F7, ApoB, proprotein convertase
subtilisin/kexin type 9 (PCKS9), sortillin 1 (SORT1), or x-box binding
protein (Xpb1). The dose of an individual siRNA was varied between
0.005 and 0.2 mg/kg, leading to a cumulative dose between 0.025
and 1.0 mg/kg. At the highest dose, all five genes were silenced
65-90%. Although this combination was not tested for its potential
to treat cholesterol-based pathologies, it did demonstrate that five
genes could be knocked down simultaneously (Fig. 7.4).
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