Biology Reference
In-Depth Information
Table 14.1
Animal studies with antisense miRNAs
Types of nuclestide
Target cell
Target miRNA
Outcome
a
Reference
2-
O
¢ -methyl cholesterol
Liver
miR-19, miR-122,
miR-192, miR-194
Down
[
19
]
2-
O
¢ -MOE
b
Liver
miR-122
Down
[
20
]
2-
O
¢ -methyl cholesterol
Liver, brain
miR-122
Down
[
25
]
2-
O
¢ -methyl cholesterol
Breast cancer cell
miR-10b
Down
[
26
]
a
Outcome means the result of target miRNA expression in target cells
b
2 ¢ -
O
-methoxyethyl phosphorothioate
Table 14.2
Animal studies with miRNA mimics
Delivery method
Target cell
Target miRNA
Outcome
a
Reference
Atelocollagen
Prostate cancer cell
miR-16
Up
[
37
]
Atelocollagen
Osteosarcoma cell
miR-143
Up
[
36
]
JetPEI
Breast cancer cell
miR-22
Up
[
38
]
Lentivirus
Lung cancer (mouse model)
b
let-7
Up
[
40
]
AAV
Liver cancer (mouse model)
b
miR-26a
Up
[
39
]
let-7: Kras
LSL-G12D
, Trp-53
fl ox/ fl ox
mice; miR-26a: tet-o-
MYC
, LAP-tTA mice
a
Outcome means the result of target miRNA expression in target cells
b
Mouse model refers to naturally arising tumors induced by transgenes
the 2¢ -
O
-oxygen is bridged to the 40-position via a methylene linker to form a rigid
bicycle, locked into a C3¢-endo(RNA) sugar conformation [
24
] . The LNA
modification leads to the thermodynamically stable duplex formation with comple-
mentary RNA.
Upon cellular transfection, AMO are incorporated into the RISC. They then bind
to the guide sequence of mature miRNAs. The consequent AMO-miRNA-RISC
complex cannot bind to the target mRNA; therefore, the function of miRNAs is
impaired. There are several types of chemical modifications, such as 2¢ -
O
-methyl,
phosphorothioate, locked nucleic acid (LNA), and peptide nucleic acids (PNA) that
can enhance the binding strength to miRNA as well as resistance to nuclease degra-
dation in vivo reducing the requirement for a protective delivery system. Indeed,
recent reports have shown miRNA suppression of ASO in vivo (Table
14.1
). The
first study of AMO injection in vivo was performed by Krutzfeldt [
22
] . In this
report, they tested in mice the effect of antagomir-122 and antagomir-16 to reduce
the expression of miR-122 in liver and miR-16 in liver, kidney, lung, heart, skin,
skeletal muscle, adrenal gland, small intestine, colon, fat, brain, and bone marrow
after tail vein injection (80 mg/kg in 0.2 ml). They found that miR-16 was repressed
in all tissues except the brain.
The second trial of AMO was focused on inhibition of miR-122 [
27
] . miR-122
inhibition was mediated by a 2¢ -
O
-methoxyethyl phosphorothioate ASO after
intraperitoneal injection (12.5-75 mg/kg ASO twice weekly for 4 weeks) in normal
mice. Reduced plasma cholesterol levels and increased hepatic fatty acid oxidation
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