核酸医薬開発の動向と課題 - nihs.go.jp

1 2013 12 13 ! ! 5 ! NIHS Since 1874 NIHS Since 1874 ! !1 2 3 = Oligonucleotide Therapeutics! * * ! ! !!! ! ! ! ! mRNA! Promoter!Gene!RISC ! 1 DNA/RNA 2 DNA siRNA! 2 RNA ! miRNA!miRNA miRNA mimic! 2 RNA ! ! DNA! ! 1 DNA/RNA Non-coding !miRNA CpG !CpG 1 DNA! ! 1 DNA/RNA ! !promoter! !

2 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 ! ! ! ! ! ! 2 Phase III Phase II III! 1 !Phase II!Phase II III!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 ! ! !

3 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 ! ! ! ! ! ! 2 Phase III Phase II III! 1 !Phase II!Phase II III!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 ! ! mRNA miRNA ! ! ! !

4 ! (~10%) ! ! ! ! ! ! ! ! (~10%) ! ! 50,000 Pegaptanib ! siRNA! 14,000! ! 7,600 Mipomersen ! ! 58,000 ! ! 150,000 or 48,000! 1,000 !! ! ! ! !!! ! ! ! ! ! ! ! ! ! !!- -! mRNA! Promoter!Gene!RISC ! 1 DNA/RNA 2 DNA siRNA! 2 RNA !

5 MiRNA!miRNA miRNA mimic! 2 RNA ! ! DNA! ! 1 DNA/RNA Non-coding !miRNA ! ! ! ! ! ! !! ! ! # ! # ! / ! !- -!1 2 3 0"10"20"30"40"50"60"70"80"90"100"1"2"3"4 " miRNA siRNA 0"10"20"30"40"50"60"70"80"90"100"1"2"3"4 " 0"10"20"30"40"50"60"70"80"90"100"1"2"3"4 " 0 20 40 60 80 100 RNA Fomivirsen Pegaptanib Mipomersen 2012 !

6 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 ! ! ! ! ! ! 2 Phase III Phase II III! 1 !Phase II!Phase II III!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 ! ! RNase H mRNA! Pre-mRNA!RNase H mRNA RNase H RNase H RNA RNase H: !

7 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 -MOE (S ) !mRNA!RNase H !mRNA ! 2 MOE 2 MOE DNA mRNA ! !DNA Fomivirsen Mipomersen DNA (S ) 1 2 2 -MOE (S ) !2 ,4 -BNA/LNA (S ) 1 Fomivirsen Vitravene) ISIS Pharmaceutical !n 1998 !n CMV) IE2 mRNA !n AIDS CMV !n !

8 N ! !n 21 Mipomersen Kynamro) ISIS Pharmaceutical !n 2013 1 !n ApoB100 mRNA !n !n !n !n 20 ! 2 2 MOE 2 MOE RNaseH G C C T C A G T C T G C T T C G C A C C RNA-like RNA-like DNA-like 2 Mipomersen Kynamro) ISIS Pharmaceutical !n 2013 1 !n ApoB100 mRNA !n !n !n !n 20 !n Gapmer !2 Deoxy!RNase H mRNA RNase H RNase H RNA mRNA! Pre-mRNA!mRNA! RNase H!RNase H: !DNA/RNA !RNA Duchenne muscular dystrophy DMD !

9 ! 3300 1 ! ! ! ! ! ! Duchenne muscular dystrophy DMD ! ! 3300 1 ! ! ! ! ! ! !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 Duchenne muscular dystrophy DMD !

10 ! 3300 1 ! ! ! ! ! 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!( ) Drisapersen: PRO051/GSK2402968!(GSK-Prosensa )! - 51! - 2 -OMe , 20 !