公开(公告)号：US20200157545A1

公开(公告)日：2020-05-21

申请号：US16618010

申请日：2018-06-01

Applicant: Chandra VARGEESE ,  Naoki IWAMOTO ,  David Charles Donnell BUTLER ,  Subramanian MARAPPAN ,  Genliang LU ,  Jason Jingxin ZHANG ,  Vinod VATHIPADIEKAL ,  Maria David FRANK-KAMENETSKY ,  Luciano Henrique APPONI ,  WAVE LIFE SCIENCES LTD.

Inventor： Chandra Vargeese ,  Naoki Iwamoto ,  David Charles Donnell Butler ,  Subramanian Marappan ,  Genliang Lu ,  Jason Jingxin Zhang ,  Vinod Vathipadiekal ,  Maria David Frank-Kamenetsky ,  Luciano Henrique Apponi ,  Young Jin Cho

IPC: C12N15/113 ,  A61K31/712

Abstract: Among other things, the present disclosure provides designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide improved single-stranded RNA interference and/or RNase H-mediated knockdown. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., RNA interference (RNAi) activity, stability, delivery, etc. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in RNA interference and/or RNase H-mediated knockdown.

公开(公告)号：US20190209604A1

公开(公告)日：2019-07-11

申请号：US16305937

申请日：2017-06-02

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： Jason Jingxin Zhang ,  Naoki Iwamoto ,  Christopher J. Francis ,  Chandra Vargeese ,  David Charles Donnell Butler ,  Sethumadhavan Divakaramenon ,  Genliang Lu ,  Subramanian Marappan

IPC: A61K31/7125 ,  C12N15/117 ,  A61P21/00

CPC classification number: A61K31/7125 ,  A61K31/7088 ,  A61P21/00 ,  C12N15/117 ,  C12N2310/17 ,  C12N2310/31 ,  C12N2310/315 ,  C12N2310/351 ,  C12N2310/3515

Abstract: The present disclosure pertains to the recognition that immune responses mediated by CpG oligonucleotides can be affected by the stereochemistry of modified internucleotidic linkages such as phosphorothioates. In some embodiments, the present disclosure relates to chirally controlled CpG oligonucleotide compositions comprising CpG oligonucleotides comprising multiple modified internucleotidic linkages such as phosphorothioate linkages, wherein the oligonucleotides comprise one or more CpG region motifs having defined stereochemistry patterns of chiral internucleotidic linkages. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are capable of agonizing an immune response. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are antagonistic. Methods for making and using chirally controlled CpG oligonucleotide compositions are also described. In some embodiments, no immune modulation is desired, and the present disclosure provides methods of identifying chirally controlled oligonucleotide compositions which have decreased immune modulation.

公开(公告)号：US10280192B2

公开(公告)日：2019-05-07

申请号：US15941494

申请日：2018-03-30

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： Gregory L. Verdine ,  Meena ,  Naoki Iwamoto ,  David Charles Donnell Butler

IPC: A61K31/66 ,  A61K31/70 ,  C07H13/04 ,  C07H21/04 ,  C07C309/66 ,  C07D295/108

Abstract: The present application, among other things, provides technologies, e.g., reagents, methods, etc. for preparing oligonucleotides comprising phosphorothiotriesters linkages. In some embodiments, provided methods comprise reacting an H-phosphonate of structure Ia or Ib with a silylating reagent to provide a silyloxyphosphonate, and reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa or IIb to provide an oligonucleotide of structure IIIa or IIIb. In some embodiments, provided methods comprise reacting an H-phosphonate of structure Ic with a silylating reagent to provide a silyloxyphosphonate, reacting the silyloxyphosphonate with a bis(thiosulfonate) reagent of structure IVc to provide a phosphorothiotriester comprising a thiosulfonate group of structure Vc, and then reacting the phosphorothiotriester comprising a thiosulfonate group of structure Vc with a nucleophile of structure VIc to provide an oligonucleotide of structure IIIc. In some embodiments, the present application provides a thiosulfonate reagent of structure IIa:

公开(公告)号：US20190106696A1

公开(公告)日：2019-04-11

申请号：US16109638

申请日：2018-08-22

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： Meena ,  David Butler ,  Naoki Iwamoto ,  Nenad Svrzikapa ,  Gregory L. Verdine ,  Ivan Zlatev

IPC: C12N15/113

Abstract: The present invention relates to chirally controlled oligonucleotides of select designs, chirally controlled oligonucleotide compositions, and methods of making and using the same. In some embodiments, a provided chirally controlled oligonucleotide composition provides different cleavage patterns of a nucleic acid polymer than a reference oligonucleotide composition. In some embodiments, a provided chirally controlled oligonucleotide composition provides single site cleavage within a complementary sequence of a nucleic acid polymer.

公开(公告)号：US20180222936A1

公开(公告)日：2018-08-09

申请号：US15941494

申请日：2018-03-30

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： Gregory L. Verdine ,  Meena ,  Naoki Iwamoto ,  David Charles Donnell Butler

IPC: C07H21/04 ,  C07H13/04 ,  A61K31/66 ,  C07C309/66 ,  A61K31/70 ,  C07D295/108

CPC classification number: C07H21/04 ,  A61K31/66 ,  A61K31/70 ,  C07C309/66 ,  C07D295/108 ,  C07H13/04

Abstract: Described herein are methods for the synthesis of derivatives of thiosulfonate reagents. Said reagents have utility for the synthesis of phosphorothiotriesters from H-phosphonates in a stereospecific fashion.

公开(公告)号：US20240174710A1

公开(公告)日：2024-05-30

申请号：US18316932

申请日：2023-05-12

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： David Charles Donnell Butler ,  Christopher P. Hencken ,  Naoki Iwamoto ,  Pachamuthu Kandasamy ,  Alvaro Andres Lanao ,  Genliang Lu ,  Mamoru Shimizu ,  Sethumadhavan Divakaramenon ,  Chandra Vargeese ,  Gopal Reddy Bommineni ,  Subramanian Marappan

IPC: C07H21/04 ,  C07C213/00 ,  C07C215/20 ,  C07C215/44 ,  C07D207/08 ,  C07D211/22 ,  C07F7/08 ,  C07F9/6564 ,  C07H19/06

CPC classification number: C07H21/04 ,  C07C213/00 ,  C07C215/20 ,  C07C215/44 ,  C07D207/08 ,  C07D211/22 ,  C07F7/0812 ,  C07F7/083 ,  C07F9/6564 ,  C07H19/06 ,  C07C2601/14

Abstract: The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.

公开(公告)号：US20240132894A1

公开(公告)日：2024-04-25

申请号：US17956741

申请日：2022-09-29

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： Chandra Vargeese ,  Naoki Iwamoto ,  David Charles Donnell Butler ,  Subramanian Marappan ,  Genliang Lu ,  Jason Jingxin Zhang ,  Vinod Vathipadiekal ,  Maria David Frank-Kamenetsky ,  Luciano Henrique Apponi ,  Young Jin Cho

IPC: C12N15/113 ,  A61K31/712

CPC classification number: C12N15/1137 ,  A61K31/712 ,  C12N2310/14 ,  C12N2310/315 ,  C12N2310/343

Abstract: Among other things, the present disclosure provides designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide improved single-stranded RNA interference and/or RNase H-mediated knockdown. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., RNA interference (RNAi) activity, stability, delivery, etc. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in RNA interference and/or RNase H-mediated knockdown.

公开(公告)号：US20230295619A1

公开(公告)日：2023-09-21

申请号：US17907895

申请日：2021-02-26

Applicant: Abbie Madeline MAGUIRE ,  Priyanka Shiva PRAKASHA ,  Naoki IWAMOTO ,  Kenneth Allan LONGO ,  Chandra VARGEESE ,  Kevin KIM ,  Elena DALE ,  Pachamuthu KANDASAMY ,  Mamoru SHIMIZU ,  WAVE LIFE SCIENCES LTD.

Inventor： Abbie Madeline Maguire ,  Priyanka Shiva Prakasha ,  Naoki Iwamoto ,  Kenneth Allan Longo ,  Chandra Vargeese ,  Kevin Kim ,  Elena Dale ,  Pachamuthu Kandasamy ,  Mamoru Shimizu

IPC: C12N15/113 ,  A61P25/28

CPC classification number: C12N15/113 ,  A61P25/28 ,  C12N2310/14 ,  C12N2310/314 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/322

Abstract: Among other things, the present disclosure provides oligonucleotides, compositions, and methods for preventing and/ or treating various conditions, disorders or diseases. In some embodiments, provided technologies comprise nucleobase modifications, sugar modifications, intemucleotidic linkage modifications and/or patterns thereof, and have improved properties, activities and/or selectivities. In some embodiments, provided technologies target MAPT. In some embodiments, the present disclosure provides MAPT oligonucleotides, compositions and methods for preventing and/or treating MAPT-associated conditions, disorders or diseases, such as Alzheimer’s Disease (AD) or Frontotemporal Dementia (FTD).

公开(公告)号：US11739325B2

公开(公告)日：2023-08-29

申请号：US16636902

申请日：2018-08-07

Applicant: WAVE LIFE SCIENCES LTD.

Inventor： Chandra Vargeese ,  Zhong Zhong ,  Naoki Iwamoto ,  Jason Jingxin Zhang ,  Jean-Cosme Dodart ,  Yuanjing Liu ,  Pachamuthu Kandasamy ,  Sethumadhavan Divakaramenon ,  Genliang Lu ,  Subramanian Marappan

IPC: C12N15/113 ,  C12N15/11 ,  C12Q1/68

CPC classification number: C12N15/113 ,  C12N15/11 ,  C12N2310/11 ,  C12N2310/12 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/33 ,  C12N2310/341 ,  C12N2310/346

Abstract: Among other things, the present disclosure provides oligonucleotides, compositions, and methods thereof. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., knockdown ability, stability, delivery, etc. In some embodiments, the oligonucleotides decrease the expression, activity and/or level of a C9orf72 gene, including but not limited to, one comprising a repeat expansion, or a gene product thereof. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in treatment of C9orf72-related disorders.

公开(公告)号：US20230220384A1

公开(公告)日：2023-07-13

申请号：US17766677

申请日：2020-10-06

Applicant: Prashant MONIAN ,  Chikdu Shakti SHIVAILA ,  Subramanian MARAPPAN ,  Chandra VARGEESE ,  Pachamuthu KANDASAMY ,  Genliang LU ,  Hui YU ,  David Charles Donnell BUTLER ,  Luciano Henrique APPONI ,  Mamoru SHIMIZU ,  Stephany Michelle STANDLEY ,  David John BOULAY ,  Andrew Guzior HOSS ,  Jigar DESAI ,  Jack David GODFREY ,  Hailin YANG ,  Naoki IWAMOTO ,  WAVE LIFE SCIENCES LTD.

Inventor： Prashant Monian ,  Chikdu Shakti Shivalila ,  Subramanian Marappan ,  Chandra Vargeese ,  Pachamuthu Kandasamy ,  Genliang Lu ,  Hui Yu ,  David Charles Donnell Butler ,  Luciano Henrique Apponi ,  Mamoru Shimizu ,  Stephany Michelle Standley ,  David John Boulay ,  Andrew Guzior Hoss ,  Jigar Desai ,  Jack David Godfrey ,  Hailin Yang ,  Naoki Iwamoto

IPC: C12N15/113

CPC classification number: C12N15/113 ,  C12N2310/14 ,  C12N2310/351 ,  C12N2310/314 ,  C12N2310/322 ,  C12N2310/321 ,  C12N2310/315

Abstract: Among other things, the present disclosure provides oligonucleotides and compositions thereof. In some embodiments, provided oligonucleotides and compositions are useful for adenosine modification. In some embodiments, the present disclosure provides methods for treating various conditions, disorders or diseases that can benefit from adenosine modification.