核酸医薬開発の動向と課題 - nihs.go.jp · PDF file多様な核酸医薬品! アンチセンス siRNA アプタマー miRNA! アンチセンス miRNA! mimic デコイ CpGオリゴ

20131213!
!5!
NIHS
Since 1874
NIHS
Since 1874
!
!

= Oligonucleotide Therapeutics! **! ! !!!! ! !
!

mRNA!
Promoter! Gene!
RISC
!1DNA/RNA
2DNA
siRNA!2RNA!
miRNA!
miRNAmiRNA mimic!
2RNA!
!
DNA!!1DNA/RNA
Non-coding
!
miRNA

CpG!CpG1DNA!
!1DNA/RNA
!!
promoter!!
TLR9!
!
PEG!
PEG!
mRNA!!PEG!
Gene!
!

!
siRNA miRNA!miRNA!mimic CpG
! 1!DNA/RNA!2!RNA!
1!DNA/RNA!
1!DNA/RNA!
2!RNA!
2!DNA!
1!DNA!
! 12-21!20-30! 20-25! 26-45! 12-16! 20-25! 20! 20!
! mRNA!Pre-mRNA! mRNA!!
! miRNA! mRNA!!
!!TLR9!
!!
mRNA!
!mRNA! ! miRNA!(miRNA)! miRNA! !
!!
!!
2Phase III Phase IIIII!
1!Phase II! Phase IIIII! Phase I! Phase II! Phase II!
!!
Isis, Santaris, Prosensa,! Sarepta !
Alnylam, Quark,!
Arrowhead
Pfizer,Regado, !NOXXON !
Santaris, Regulus!
MiRagen, Mirna!
Anges-MG,!Adynxx!
Pfizer, Dynavax !
! !! !PEG!
! Miravirsen! !NF-B,!AYX-1!
!

mRNAmiRNA! !
!
!
!
(~10%)
!
!
!!
!!
!
!
(~10%)

!
!50,000Pegaptanib!siRNA !14,000! ! 7,600Mipomersen! !58,000! !150,000or 48,000! 1,000!
!!!!! ! !! !!

!
!!!!!
!!
- -!

mRNA!
Promoter! Gene!
RISC
!1DNA/RNA
2DNA
siRNA!2RNA!
miRNA!
miRNAmiRNA mimic!
2RNA!
!
DNA!!1DNA/RNA
Non-coding
!
miRNA

!
!!!!!
!!! !# !# !
/!!
- -!

0"
10"
20"
30"
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100"
1" 2" 3" 4"
miRNAsiRNA
0"
10"
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1" 2" 3" 4"0"
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1" 2" 3" 4"
0
20
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RNA
Fomivirsen PegaptanibMipomersen
2012

!
! 1!DNA/RNA!2!RNA!
1!DNA/RNA!
1!DNA/RNA!
2!RNA!
2!DNA!
1!DNA!
! 12-21!20-30! 20-25! 26-45! 12-16! 20-25! 20! 20!
! miRNA! mRNA!!
!!TLR9!
!!
mRNA!
!!
!!
!!
Alnylam, Quark,!
Arrowhead
Santaris, Regulus!
MiRagen, Mirna!
Anges-MG,!Adynxx!
Pfizer, Dynavax !
! !! !PEG!
!

RNaseH
mRNA! Pre-mRNA!

RNaseHmRNA
RNaseH
RNaseHRNA
RNase H: !DNA/RNA!RNA
mRNA! Pre-mRNA!
mRNA!
RNase H!

! ! !! RNA ! ! ! ! ! ! !! ! ! ! ! ! !OK! ! ! ! ! ! ! ! !!!
!RNase H !

!!
mRNA= !
Fomivirsen Mipomersen
DNA (S) 2,4-BNA/LNA (S)
1 2 2.5
2-MOE (S)
!

mRNA!
RNase H !mRNA!
2MOE 2MOE DNA
mRNA!!
DNA
Fomivirsen Mipomersen
DNA (S)
1 2 2.5
2-MOE (S)
!
2,4-BNA/LNA (S)

1
FomivirsenVitravene) ISIS Pharmaceutical!n 1998!
n CMV)IE2mRNA!
n AIDSCMV!
n 6.6mg/ml!
n !!n 21

MipomersenKynamro) ISIS Pharmaceutical!n 20131!
n ApoB100 mRNA !
n !
n !
n !
n 20!
2

2MOE 2MOE RNaseH
GCCTCAGTCTGCTTCGCACC RNA-like RNA-like DNA-like
2
MipomersenKynamro) ISIS Pharmaceutical!n 20131!
n ApoB100 mRNA !
n !
n !
n !
n 20!
n Gapmer
!2Deoxy!

RNaseHmRNA
RNaseH
RNaseHRNA
mRNA! Pre-mRNA!
mRNA!
RNase H!RNase H: !DNA/RNA!RNA

Duchenne muscular dystrophyDMD! ! 33001! ! ! !
!
!

!
!
!
1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36
37 38 39 40 41 42 43 44 45 46 47 48
49 50 51 52 53 54 55 56 57 58 59 60
61 62 63 64 65 66 67 68 69 70 71 72
73 74 75 76 77 78 79

!
50!!
!
1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36
37 38 39 40 41 42 43 44 45 46 47 48
49 51 52 53 54 55 56 57 58 59 60
61 62 63 64 65 66 67 68 69 70 71 72
73 74 75 76 77 78 79

!
N Engl J Med. 357, 2677-2686, 2007
ESE (Exonic splicing enhancer)

Human-transcriptome DataBase for Alternative Splicing!(http://www.h-invitational.jp/h-dbas/index.jsp)

Drisapersen: PRO051/GSK2402968!(GSK-Prosensa)! - 51! - 2-OMe, 20! - Phase ! - 1 6mg/kg!!!!Eteplirsen: AVI-4658!(Sarepta Therapeutics! - 51! - , 30! - Phase b! -1 30mg/kgor 50mg/kg!
!
2
2-MOE (S)
2-OMe (S)
HP !(http://www.funakoshi.co.jp/contents/699)

!!
- 53NS-065/NCNP-01!
- !
- ! !
!
!!!
- 45!
- ENA! 2-O,4-C-Ethylene-bridged Nucleic Acids!
- !
!
! !!
%
1! 51! 13.0!2! 45! 8.1!3! 53! 7.7!
4! 44! 6.2!
5! 46 4.3!
6! 52! 4.1!
7! 50! 4.0!8! 43! 3.8!
1-8! ! 51.2!

DDS
n Fomivirsen!
n Mipomersen!
n
n 1!
!n!n!

!
! 1!DNA/RNA!2!RNA!
1!DNA/RNA!
1!DNA/RNA!
2!RNA!
2!DNA!
1!DNA!
! 12-21!20-30! 20-25! 26-45! 12-16! 20-25! 20! 20!
! miRNA! mRNA!!
!!TLR9!
!!
mRNA!
!!
!!
!!
Alnylam, Quark,!
Arrowhead
Santaris, Regulus!
MiRagen, Mirna!
Anges-MG,!Adynxx!
Pfizer, Dynavax !
! !! !PEG!
!

The AAPS Journal, 12, 51-60, 2010
siRNAmiRNA

siRNA!PF-655 (Quark Pharmaceuticals! - Naked siRNA, ! - RTP801! - ! - Phase II!!ALN-RSV01 (Alnylam! - Naked siRNA, ! - Nucleocapsid! - RSV! - Phase II!!ALN-TTR02 (Alnylam! - Lipid nanoparticle (LNP), ! - TTR! - ! - Phase II Phase III!
LNPTekmira!SNALPstable nucleic acid-lipid particles!ED50: 0.02-0.1 mg/kg

ND-L02-s0201/Quark Pharmaceuticals!- Vitamin A-coupled liposomes, !- HSP47! - ! - Phase I! - siRNA! - !
siRNA!

2 O-Methyl 2 F
siRNA, ,
BNALNA
siRNA,
S
OSsiRNA, , , CpG
siRNA, , , CpG
siRNA,
PEG siRNA, , CpG
- GalNAc-conjugated siRNA!- Phase I!- Naked!- ED50: 0.5-0.2 mg/kg
ALN-TTRsc (Alnylam!
AlnylamHP

!
! 1!DNA/RNA!2!RNA!
1!DNA/RNA!
1!DNA/RNA!
2!RNA!
2!DNA!
1!DNA!
! 12-21!20-30! 20-25! 26-45! 12-16! 20-25! 20! 20!
! miRNA! mRNA!!
!!TLR9!
!!
mRNA!
!!
!!
!!
Alnylam, Quark,!
Arrowhead
Santaris, Regulus!
MiRagen, Mirna!
Anges-MG,!Adynxx!
Pfizer, Dynavax !
! !! !PEG!
!
! !

The AAPS Journal, 12, 51-60, 2010
miRNA!
miRNA mim

Documents

核酸医薬開発の動向と課題 - nihs.go.jp · PDF file多様な核酸医薬品! アンチセンス siRNA アプタマー miRNA! アンチセンス miRNA! mimic デコイ CpGオリゴ