Lipid-Like Delivery Materials for Efficient siRNA Delivery - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 165

1.4

PCSK9
ApoB
FVII

1.2

1.0

Xbp1

0.8

SORT1

0.6

0.4

0.2

0.0

0.001 0.01 0.1 1

Does of each siRNA (mg/kg)

Figure 7.4 Five hepatocellular gene targets were simultaneously silenced

byasingleinjectionofpooledsiRNAsformulatedwithC12-200.
Micewereadministeredasingledoseanddosagewastitrated
from 0.2 and .005mg/kg per siRNA. 72h post injection, liver
tissue was harvested for analysis of gene transcript levels.
(s.d., n =5).ReproducedwithpermissionfromRef.[20].

investigate
whetherhighersiRNAdosesresultedinextendedsilencing.F7was
measuredasafunctionoftimeafterintravenousdosingofmiceat
0.1 and 1.0 mg/kg. Serum levels returned to baseline after 20 and
35daysattheserespectivedoses.TheseresultsillustratethatsiRNA
therapies can be tailored to diseases as they evolve over time. For
example, as inflammatory responses advance from acute to chronic,
the expression levels of the genes responsible for driving disease
progression change.

The therapeutic window also enabled us to

24

A low dose of siRNA targeting innate cell
recruitment (important in acute inflammation) could be given in
concertwithahighdosetargetingadaptivecytokinesignaling,which
isimportantinbothacuteandchronicstages.

25

Similarly,cancercells
often upregulate drug efflux pumps and different metabolic genes in
response to treatment with chemotherapy.

26

Increased expression
of these “contingency” genes allows cells to survive, leading to
diseaseremission.siRNAstargetingtraditionaloncogenescouldbe
combined with siRNAs targeting such contingency genes, thereby
enhancing the efficacy of co-administered small molecule drugs.