公开(公告)号：EP3004347B1

公开(公告)日：2018-09-26

申请号：EP14804901.8

申请日：2014-05-30

申请人： National University Corporation Tokyo Medical and Dental University

发明人： YOKOTA, Takanori ,  NISHINA, Kazutaka ,  YOSHIOKA, Kotaro ,  MIZUSAWA, Hidehiro

IPC分类号： C12N15/113

CPC分类号： C12N15/113 ,  C12N2310/113 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/3515 ,  C12N2310/3521

摘要： Disclosed are double-stranded nucleic acid agents that can deliver a therapeutic oligonucleotide within a biological sample, and methods for using the same. In one embodiment, the double-stranded nucleic acid agent comprises a first strand comprising a first RNA region, and a second strand comprising a first DNA region, wherein said first RNA region and said first DNA region are hybridized as a RNA/DNA heteroduplex. Said first strand further comprises a nucleic acid therapeutic oligonucleotide region that is capable of being cleaved from at least one nucleotide in said first RNA region. Methods for using the double-stranded nucleic acid agents include methods for delivering the therapeutic oligonucleotide as a single strand by cleaving it from at least a portion of the first RNA region. The methods further include delivering the double-stranded nucleic acid agent and thus the therapeutic oligonucleotide to a target site within the body of a treatment subject.

公开(公告)号：EP2791335A1

公开(公告)日：2014-10-22

申请号：EP12815856.5

申请日：2012-12-17

申请人： National University Corporation Tokyo Medical and Dental University ,  Osaka University

发明人： YOKOTA, Takanori ,  NISHINA, Kazutaka ,  OBIKA, Satoshi ,  MIZUSAWA, Hidehiro

IPC分类号： C12N15/11 ,  C12N15/113 ,  A61K31/713

CPC分类号： C12N15/113 ,  C12N15/111 ,  C12N2310/11 ,  C12N2310/15 ,  C12N2310/3181 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/3513 ,  C12N2310/3515 ,  C12N2310/53 ,  C12N2320/52

摘要： A method of reducing the level of a transcription product in a cell comprising contacting with the cell a composition comprising a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand hybridizes to the transcription product and comprises (a) a region consisting of at least 4 consecutive nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, (b) one or more nucleotide analogs located on 5′ terminal side of the region, (c) one or more nucleotide analogs located on 3′ terminal side of the region and (d) a total number of nucleotides and nucleotide analogs ranging from 8 to 35 nucleotides and (ii) the second nucleic acid strand comprises (a) nucleotides and optionally nucleotide analogs and (b) at least 4 consecutive RNA nucleotides.

摘要翻译： 一种降低细胞中转录产物水平的方法，包括使细胞与包含退火至第二核酸链的第一核酸链的双链核酸复合物组合物接触，其中：（i）第一核酸 酸链与转录产物杂交，并且包含（a）当该链与转录产物杂交时由至少4个连续核苷酸被核糖核酸酶H识别的区域，（b）位于5'末端的一个或多个核苷酸类似物 （c）位于该区域的3'末端侧的一个或多个核苷酸类似物和（d）8至35个核苷酸的核苷酸和核苷酸类似物的总数，以及（ii）第二核酸链包含 （a）核苷酸和任选的核苷酸类似物和（b）至少4个连续的RNA核苷酸。

公开(公告)号：EP4306572A1

公开(公告)日：2024-01-17

申请号：EP22767063.5

申请日：2022-03-07

申请人： AGC INC. ,  The University of Tokyo ,  National University Corporation Tokyo Medical and Dental University

发明人： HARA, Mihoko ,  HARA, Rintaro ,  MIYATA, Kanjiro ,  NAITO, Mitsuru ,  YOKOTA, Takanori

IPC分类号： C08G69/48 ,  A61K31/7088 ,  A61K45/00 ,  A61K47/34 ,  A61K47/42 ,  A61K47/59 ,  A61K47/60 ,  A61K47/64 ,  A61K48/00 ,  A61P43/00

摘要： The present invention provides a polymer represented by the following formula (I):

wherein each symbol is as described in the specification, which is useful as a drug carrier in effectively delivering a drug to a target site.

公开(公告)号：EP4032551A1

公开(公告)日：2022-07-27

申请号：EP20864622.4

申请日：2020-09-16

申请人： National University Corporation Tokyo Medical and Dental University ,  Takeda Pharmaceutical Company Limited

发明人： YOKOTA, Takanori ,  NAGATA, Tetsuya ,  FURUKAWA, Hideki ,  YOGO, Takatoshi ,  NAKAGAWA, Yasuo ,  SASAKI, Shigekazu ,  TOKUNOH, Ryosuke ,  SEKI, Tomohiro ,  HIDAKA, Kosuke ,  KIKUCHI, Fumiaki ,  KUBO, Osamu ,  KASAHARA, Takahito ,  KOJIMA, Takuto ,  WANG, Junsi ,  TOKUNAGA, Norihito

IPC分类号： A61K48/00 ,  A61P25/00 ,  A61P43/00 ,  C12N5/079 ,  C12N5/10 ,  A61K47/54 ,  C12N15/113 ,  A61K31/713

摘要： The object of the present invention is to provide a nucleic acid agent that is efficiently delivered to the nervous system, for example, the central nervous system to which drug delivery can be prevented by BBB, and produces an antisense effect on the target transcriptional product at the delivery site, and a composition comprising the same. In an embodiment, the present invention provides a double-stranded nucleic acid complex formed by annealing a first nucleic acid strand that hybridizes to a part of a target transcriptional product and has an antisense effect on the target transcriptional product, and a second nucleic acid strand that comprises a base sequence complementary to the first nucleic acid strand and is bound to a C 22-35 alkyl group optionally substituted with a hydroxy group or an analog thereof.

公开(公告)号：EP2791335B1

公开(公告)日：2018-11-14

申请号：EP12815856.5

申请日：2012-12-17

申请人： National University Corporation Tokyo Medical and Dental University ,  Osaka University

发明人： YOKOTA, Takanori ,  NISHINA, Kazutaka ,  OBIKA, Satoshi ,  MIZUSAWA, Hidehiro

IPC分类号： C12N15/11 ,  C12N15/113 ,  A61K31/713

CPC分类号： C12N15/113 ,  C12N15/111 ,  C12N2310/11 ,  C12N2310/15 ,  C12N2310/3181 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/3513 ,  C12N2310/3515 ,  C12N2310/53 ,  C12N2320/52

摘要： A method of reducing the level of a transcription product in a cell comprising contacting with the cell a composition comprising a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand hybridizes to the transcription product and comprises (a) a region consisting of at least 4 consecutive nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, (b) one or more nucleotide analogs located on 5′ terminal side of the region, (c) one or more nucleotide analogs located on 3′ terminal side of the region and (d) a total number of nucleotides and nucleotide analogs ranging from 8 to 35 nucleotides and (ii) the second nucleic acid strand comprises (a) nucleotides and optionally nucleotide analogs and (b) at least 4 consecutive RNA nucleotides.

公开(公告)号：EP3954395A1

公开(公告)日：2022-02-16

申请号：EP20788494.1

申请日：2020-04-08

申请人： National University Corporation Tokyo Medical and Dental University

发明人： YOKOTA, Takanori ,  NAGATA, Tetsuya

IPC分类号： A61K48/00 ,  A61P3/10 ,  A61P7/00 ,  A61P9/00 ,  A61P9/06 ,  A61P21/00 ,  A61P21/04 ,  A61P25/28 ,  A61P29/00 ,  A61K47/56 ,  C12N15/113 ,  A61K31/713

摘要： A nucleic acid complex that exhibits an excellent antisense effect in the skeletal muscle and/or heart muscle, and a composition for treating or preventing a muscle disease that develops in the skeletal muscle, heart muscle, and the like comprising the nucleic acid complex as an active ingredient is to be developed. A double-stranded nucleic acid complex in which a first nucleic acid strand that hybridizes to the transcription product of a target gene and has an antisense effect on the transcription product is annealed with a second nucleic acid strand that comprises a base sequence complementary to the first nucleic acid strand and is bound to cholesterol or analog thereof is provided.

公开(公告)号：EP3766972A1

公开(公告)日：2021-01-20

申请号：EP19767189.4

申请日：2019-03-13

申请人： National University Corporation Tokyo Medical and Dental University ,  Takeda Pharmaceutical Company Limited

发明人： YOKOTA, Takanori ,  NAGATA, Tetsuya ,  FURUKAWA, Hideki ,  NAKAGAWA, Yasuo ,  YOGO, Takatoshi ,  TOKUNOH, Ryosuke ,  SASAKI, Shigekazu ,  HIDAKA, Kosuke ,  SEKI, Tomohiro ,  MIYATA, Kenichi ,  UCHIDA, Akio

IPC分类号： C12N15/113 ,  A61K31/711 ,  A61K31/713 ,  A61K47/54 ,  A61K48/00 ,  A61P25/00

摘要： Developed and provided is: a nucleic acid agent that is efficiently delivered to the central nervous system, to which drug delivery is inhibited by the blood brain barrier mechanism, and that provides an antisense effect to a target transcription product at the delivery site; and a composition containing such a nucleic acid agent.
Provided is a double-stranded nucleic acid complex consisting of a first nucleic acid strand and a second nucleic acid strand that are annealed to each other; wherein the first nucleic acid strand hybridizes with part of a target transcription product and has an antisense effect on the target transcription product; and wherein the second nucleic acid strand includes a base sequence complementary to the first nucleic acid strand and is conjugated to a phosphatidylethanolamine or an analog thereof.

公开(公告)号：EP3004347A1

公开(公告)日：2016-04-13

申请号：EP14804901.8

申请日：2014-05-30

申请人： National University Corporation Tokyo Medical and Dental University

发明人： YOKOTA, Takanori ,  NISHINA, Kazutaka ,  YOSHIOKA, Kotaro ,  MIZUSAWA, Hidehiro

IPC分类号： C12N15/09

CPC分类号： C12N15/113 ,  C12N2310/113 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/3515 ,  C12N2310/3521

摘要： Disclosed are double-stranded nucleic acid agents that can deliver a therapeutic oligonucleotide within a biological sample, and methods for using the same. In one embodiment, the double-stranded nucleic acid agent comprises a first strand comprising a first RNA region, and a second strand comprising a first DNA region, wherein said first RNA region and said first DNA region are hybridized as a RNA/DNA heteroduplex. Said first strand further comprises a nucleic acid therapeutic oligonucleotide region that is capable of being cleaved from at least one nucleotide in said first RNA region. Methods for using the double-stranded nucleic acid agents include methods for delivering the therapeutic oligonucleotide as a single strand by cleaving it from at least a portion of the first RNA region. The methods further include delivering the double-stranded nucleic acid agent and thus the therapeutic oligonucleotide to a target site within the body of a treatment subject.

公开(公告)号：EP2961841A1

公开(公告)日：2016-01-06

申请号：EP14757511.2

申请日：2014-03-03

申请人： National University Corporation Tokyo Medical and Dental University

发明人： YOKOTA, Takanori ,  NISHINA, Kazutaka ,  MIZUSAWA, Hidehiro ,  WADA, Takeshi

IPC分类号： C12N15/09 ,  A61K31/7088 ,  A61K48/00 ,  A61P43/00

CPC分类号： C12N15/113 ,  A61K31/7088 ,  A61K31/712 ,  A61K31/7125 ,  A61K31/713 ,  C12N15/111 ,  C12N2310/11 ,  C12N2310/14 ,  C12N2310/315 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/53 ,  C12N2310/533

摘要： Chimeric single-stranded polynucleotides and double-stranded antisense agents useful for modifying the expression of a target gene by means of an antisense effect are disclosed. The chimeric single-stranded antisense polynucleotide and double-stranded antisense agents comprise a central nucleotide region flanked by a first 5'-wing region and a first 3'-wing region of modified nucleotides, which are themselves flanked by a second 5'-wing region and/or a second 3'-wing region of nucleotides that have a low affinity for proteins and/or that have higher resistance to DNase or RNase than a natural DNA or RNA and are missing in a cell when the chimeric polynucleotide delivered. The double-stranded antisense agent further comprises a complementary strand annealed to the antisense strand. The polynucleotide can be used to modify RNA transcription levels, miRNA activity, or protein levels in cells.

公开(公告)号：EP3928799A1

公开(公告)日：2021-12-29

申请号：EP20758455.8

申请日：2020-02-20

申请人： National University Corporation Tokyo Medical and Dental University

发明人： YOKOTA, Takanori ,  HARA, Rintaro ,  NAGATA, Tetsuya ,  KIZAWA, Hideki ,  TAKAGI, Koh

IPC分类号： A61K48/00 ,  C12N15/113 ,  A61K31/711

摘要： An object of the present invention is to provide a double-stranded nucleic acid complex having a reduced number of PS modifications in an antisense strand and maintaining an antisense effect. An optimal PS modification pattern for double-stranded nucleic acid complexes is disclosed. Such a nucleic acid complex comprising an antisense strand having an optimal PS modification pattern has a characteristic of having low toxicity and high bioavailability. The double-stranded nucleic acid complex comprising an antisense strand having an optimal PS modification pattern according to the present invention is useful when used as a nucleic acid drug that utilizes inhibition of expression of a specific gene (knockdown), activity that changes the function of coating or non-coding RNA for a specific gene, or activity that changes the function of RNA by inducing exon skipping during processing of pre-mRNA for a specific gene.