DK2788487T3 - Oligonukleotidanaloger målrettet mod human lmna - Google Patents

Oligonukleotidanaloger målrettet mod human lmna Download PDF

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DK2788487T3
DK2788487T3 DK12805882.3T DK12805882T DK2788487T3 DK 2788487 T3 DK2788487 T3 DK 2788487T3 DK 12805882 T DK12805882 T DK 12805882T DK 2788487 T3 DK2788487 T3 DK 2788487T3
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Richard Keith Bestwick
Ryszard Kole
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Claims (13)

1. Antisense-oligonukleotid til reducering af ekspressionen af anormalt splejset LMNA-mRNA, hvilket oligonukleotid har en i det væsentlige uladet rygrad og består af morpholino-subunits og phorphorholdige intersubunit-bindinger, der kobler et morpholino-nitrogen på én subunit til et 5'-exocyklisk carbon på en tilstødende subunit, indeholder 25-40 baser og omfatter en målretningssekvens, der omfatter en hvilken som helst af SEQ ID NO: 4, 5, 10, 11, 13, 14 og 16, hvor antisense-oligonukleotidet er kovalent bundet til et cellepenetrerende peptid og en linkerdel, hvor linkerdelen er valgt blandt glycin, cystein, prolin, 6-aminohexansyre (Ahx), β-alanin (B) og Ahx-B, og det cellepenetrerende peptid er valgt blandt SEQ ID NO: 39-54.
2. Oligonukleotid ifølge krav 1, hvor morpholino-subunittene i oligonukleotidet er koblet ved hjælp af phorphorholdige bindinger i henhold til følgende struktur:
hvor Z er S eller O, X = NR4R2 eller OR6, Y = O eller NR7, Pj er en purin- eller pyrimidin-baseparrende del, og hver binding er valgt blandt: (a) en uladet binding (a) , hvor hver af R1, R2, R6 og R7 er valgt uafhængigt blandt hydrogen og en lavere alkyl; (bl) en kationisk binding (bl) , hvor X = NR1R2 og Y = O, og NR4R2 er en eventuelt substitueret piperazinogruppe, således at R1R2 = -CHRCHRN (R3) (R4) CHRCHR-, hvor hver R4 er H, CH3 eller nul, og R3 er valgt blandt H, en lavere alkyl, C(=NH)NH2, Z-L-NHC(=NH)NH2 og [C (O) CHR' NH] mH, hvor L, hvis Z er carbonyl (C (O) ) eller en direkte binding, er en eventuel linker med en længde på op til 18 atomer, der har bindinger valgt blandt alkyl, alkoxy og alkylamino, R' er en sidekæde på en naturligt forekommende aminosyre eller en én- eller to-carbonhomolog dertil, og m er 1 til 6; (b2) en kationisk binding (b2), hvor X = NR1R2 og Y = 0, R1 = H eller CH3 og R2 = LNR3R4R5, hvor L, R3 og R4 er som defineret ovenfor, og R5 er H, en lavere alkyl eller en lavere (alkoxy)alkyl; og (b3) en kationisk binding (b3), hvor Y = NR7 og X = OR6 og R7 = LNR3R4R5, hvor L, R3 og R4 og R5 er som defineret ovenfor, og R6 er H eller en lavere alkyl; og mindst én binding er valgt blandt kationisk binding (bl), (b2) og (b3).
3. Oligonukleotid ifølge krav 2, hvor (i) hver af R1 og R2 i bindinger af type (a) er methyl; (ii) mindst én binding er af type (bl), hvor hver R er H, R4 er H, CH3 eller et elektronpar, og R3 er valgt blandt H, CH3, C(=NH)NH2 og C (0)-L-NHC (=NH)NH2; (iii) mindst én binding er af type (bl), hvor hver R er H, R4 er et elektronpar, og R3 er valgt blandt C(=NH)NH2 og C(0)-L-NHC (=NH) NH2 ; (iv) mindst én binding er af type (bl), hvor hver R er H, R4 er et elektronpar, og R3 er valgt blandt C(=NH)NH2 og C(0)-L-NHC (=NH) NH2, og eventuelt hvor R3 er C (0)-L-NHC (NH) NH2, og L er et carbonhydrid med strukturen -(CH2)n-, hvor n er 1 til 12; eller (v) mindst én binding er af type (bl), hvor hver R er H, og hver af R3 og R4 er uafhængigt H eller CH3.
4. Oligonukleotid ifølge et hvilket som helst af kravene 1-3, hvor det cellepenetrerende peptid er bundet i dets C-terminal til 5'-enden eller 3'-enden af oligonukleotidet via linkerdelen.
5. Antisense-oligonukleotid, hvor oligonukleotidet reducerer ekspressionen af anormalt splejset LMNA-mRNA, hvilket oligonukleotid omfatter en rygrad, og rygraden omfatter en sekvens af morpholino-ringstrukturer, der er koblet ved hjælp af intersubunit-bindinger, hvilke intersubunit-bindinger kobler en 3'-ende af én morpholino-ringstruktur til en 5'-ende af en tilstødende morpholino-ringstruktur, hvor hver morpholino-ringstruktur er bundet til en baseparrende del, således at oligonukleotidet kan binde på en sekvensspecifik måde til en målnukleinsyre, som omfatter en målretningssekvens, der omfatter en hvilken som helst af SEQ ID NO: 4, 5, 10, 11, 13, 14 og 16, hvor intersubunit-bindingerne har følgende generelle struktur (I):
(i) eller et salt eller en isomer deraf, og hvor hver af intersubunit-bindingerne (I) uafhængigt er binding (A) eller binding (B): hvor for binding (A) : W ved hver forekomst uafhængigt er S eller O; X ved hver forekomst uafhængigt er -N(CH3)2, -NR1R2, -OR3 eller;
(TT) Y ved hver forekomst uafhængigt er O eller -NR2, R1 ved hver forekomst uafhængigt er hydrogen eller methyl; R2 ved hver forekomst uafhængigt er hydrogen eller -LNR4R5R7; R3 ved hver forekomst uafhængigt er hydrogen eller Ci-C6alkyl; R4 ved hver forekomst uafhængigt er hydrogen, methyl, C(=NH)NH2, -Z-L-NHC (=NH)NH2 eller - [C (0) CHR' NH] mH, hvor Z er carbonyl(C(0) ) eller en direkte binding, R' er en sidekæde på en naturligt forekommende aminosyre eller en én- eller to-carbonhomolog dertil, og m er 1 til 6; R5 ved hver forekomst uafhængigt er hydrogen, methyl eller et elektronpar; R6 ved hver forekomst uafhængigt er hydrogen eller methyl; R7 ved hver forekomst uafhængigt er hydrogen, Ci-C6alkyl eller Ci-C6alkoxyalkyl; L er en eventuel linker med en længde på op til 18 atomer, der omfatter alkyl-, alkoxy- eller alkylaminogrupper eller kombinationer deraf; og hvor for binding (B): W ved hver forekomst uafhængigt er S eller 0; X ved hver forekomst uafhængigt er -NR8R9 eller -OR3; og Y ved hver forekomst uafhængigt er 0 eller -NR10, eller Y og W hver er 0, R8 ved hver forekomst uafhængigt er hydrogen eller C2-Ci2alkyl; R9 ved hver forekomst uafhængigt er hydrogen, Ci-Ci2alkyl, Ci-Ci2aralkyl eller aryl; R10 ved hver forekomst uafhængigt er hydrogen, Ci-Ci2alkyl eller -LNR4R5R7; hvor R8 og R9 kan bindes sammen til frembringelse af en 5-18-leddet mono- eller bicyklisk heterocyclyl, eller R8, R9 eller R3 kan bindes sammen med R10 til frembringelse af en 5-7-leddet heterocyclyl, og hvor X har følgende struktur (III), når X er 4-piparazino:
(III) hvor: R11 ved hver forekomst uafhængigt er C2-Ci2alkyl, Ci- Ci2aminoalkyl, Ci-Ci2alkylcarbonyl, aryl, heteroaryl eller heterocyclyl; og R ved hver forekomst uafhængigt er et elektronpar, hydrogen eller Ci-Ci2alkyl; og R12 ved hver forekomst uafhængigt er hydrogen, Ci-Ci2alkyl, Ci-Ci2aminoalkyl, -NH2, -NR13R14, -NR13R14R15, Ci-Ci2alkylcarbonyl, oxo, -CN, trifluormethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholat, deoxycholat, aryl, heteroaryl, heterocyclyl, -SR13 eller Ci-Ci2alkoxy, hvor R13, R14 og R15 ved hver forekomst uafhængigt er Ci-Ci2alkyl; hvor mindst én of intersubunit-bindingerne er binding (B) , eller hvor hver binding (B) , hvis den er til stede, har den samme struktur ved hver forekomst; og hvor antisense-oligonukleotidet er kovalent bundet til et cellepenetrerende peptid og en linkerdel, hvor linkerdelen er valgt blandt glycin, cystein, prolin, 6-aminohexansyre (Ahx), β-alanin (B) og Ahx-B, og det cellepenetrerende peptid er valgt blandt SEQ ID NO: 39-54.
6. Oligonukleotid ifølge et hvilket som helst af kravene 1- 5, hvor målretningssekvensen består af en hvilken som helst af SEQ ID NO: 4, 5, 10, 11, 13, 14 og 16.
7. Oligonukleotid ifølge et hvilket som helst af kravene 1- 6, hvor målretningssekvensen er SEQ ID NO: 4.
8. Oligonukleotid ifølge et hvilket som helst af kravene 1-6, hvor målretningssekvensen er SEQ ID NO: 5.
9. Oligonukleotid ifølge et hvilket som helst af kravene 1-6, hvor målretningssekvensen er SEQ ID NO: 10.
10. Oligonukleotid ifølge et hvilket som helst af kravene 1-6, hvor målretningssekvensen er SEQ ID NO: 11.
11. Oligonukleotid ifølge et hvilket som helst af kravene 1-6, hvor målretningssekvensen er SEQ ID NO: 13.
12. Oligonukleotid ifølge et hvilket som helst af kravene 1-6, hvor målretningssekvensen er SEQ ID NO: 14.
13. Oligonukleotid ifølge et hvilket som helst af kravene 1-6, hvor målretningssekvensen er SEQ ID NO: 16.
DK12805882.3T 2011-12-08 2012-12-07 Oligonukleotidanaloger målrettet mod human lmna DK2788487T3 (da)

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Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067571B2 (en) 2005-07-13 2011-11-29 Avi Biopharma, Inc. Antibacterial antisense oligonucleotide and method
AU2011257980B2 (en) 2010-05-28 2016-06-30 Sarepta Therapeutics, Inc. Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups
WO2012031243A2 (en) 2010-09-03 2012-03-08 Avi Biopharma, Inc. dsRNA MOLECULES COMPRISING OLIGONUCLEOTIDE ANALOGS HAVING MODIFIED INTERSUBUNIT LINKAGES AND/OR TERMINAL GROUPS
KR102271212B1 (ko) 2011-11-18 2021-07-01 사렙타 쎄러퓨틱스, 인코퍼레이티드 기능적으로-변형된 올리고뉴클레오티드 및 이의 서브유니트
HUE038369T2 (hu) 2011-12-08 2018-10-29 Sarepta Therapeutics Inc Humán LMNA-t célzó oligonukleotid-analógok
US20150044192A1 (en) 2013-08-09 2015-02-12 President And Fellows Of Harvard College Methods for identifying a target site of a cas9 nuclease
US20150197534A1 (en) * 2013-09-05 2015-07-16 Sarepta Therapeutics, Inc. Antisense-induced exon2 inclusion in acid alpha-glucosidase
US9340799B2 (en) 2013-09-06 2016-05-17 President And Fellows Of Harvard College MRNA-sensing switchable gRNAs
US10517869B2 (en) 2013-12-24 2019-12-31 Sentiss Pharma Private Limited Topical brimonidine tartrate ophthalmic solution
WO2016022363A2 (en) 2014-07-30 2016-02-11 President And Fellows Of Harvard College Cas9 proteins including ligand-dependent inteins
WO2016187425A1 (en) 2015-05-19 2016-11-24 Sarepta Therapeutics, Inc. Peptide oligonucleotide conjugates
EP3851531A1 (en) * 2015-06-01 2021-07-21 Sarepta Therapeutics, Inc. Antisense-induced exon exclusion in type vii collagen
US11020417B2 (en) 2015-06-04 2021-06-01 Sarepta Therapeutics, Inc Methods and compounds for treatment of lymphocyte-related diseases and conditions
KR102329187B1 (ko) * 2016-04-29 2021-11-22 사렙타 쎄러퓨틱스, 인코퍼레이티드 인간 lmna를 표적화하는 올리고뉴클레오타이드 유사체
WO2018027078A1 (en) 2016-08-03 2018-02-08 President And Fellows Of Harard College Adenosine nucleobase editors and uses thereof
US11661590B2 (en) 2016-08-09 2023-05-30 President And Fellows Of Harvard College Programmable CAS9-recombinase fusion proteins and uses thereof
US11542509B2 (en) 2016-08-24 2023-01-03 President And Fellows Of Harvard College Incorporation of unnatural amino acids into proteins using base editing
WO2018071868A1 (en) 2016-10-14 2018-04-19 President And Fellows Of Harvard College Aav delivery of nucleobase editors
WO2018119359A1 (en) 2016-12-23 2018-06-28 President And Fellows Of Harvard College Editing of ccr5 receptor gene to protect against hiv infection
WO2018165504A1 (en) 2017-03-09 2018-09-13 President And Fellows Of Harvard College Suppression of pain by gene editing
KR20190127797A (ko) 2017-03-10 2019-11-13 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 시토신에서 구아닌으로의 염기 편집제
CN110536964A (zh) * 2017-03-10 2019-12-03 国立研究开发法人国立成育医疗研究中心 反义寡核苷酸和糖原贮积病Ia型预防或治疗用组合物
CA3057192A1 (en) 2017-03-23 2018-09-27 President And Fellows Of Harvard College Nucleobase editors comprising nucleic acid programmable dna binding proteins
US11560566B2 (en) 2017-05-12 2023-01-24 President And Fellows Of Harvard College Aptazyme-embedded guide RNAs for use with CRISPR-Cas9 in genome editing and transcriptional activation
WO2018212271A1 (ja) * 2017-05-18 2018-11-22 国立大学法人京都大学 脊髄小脳変性症３６型の予防又は治療用組成物
US11732274B2 (en) 2017-07-28 2023-08-22 President And Fellows Of Harvard College Methods and compositions for evolving base editors using phage-assisted continuous evolution (PACE)
US11319532B2 (en) 2017-08-30 2022-05-03 President And Fellows Of Harvard College High efficiency base editors comprising Gam
CA3082251A1 (en) 2017-10-16 2019-04-25 The Broad Institute, Inc. Uses of adenosine base editors
KR20210130854A (ko) * 2018-03-09 2021-11-01 다이이찌 산쿄 가부시키가이샤 당원병 Ia형 치료약
WO2020051360A1 (en) * 2018-09-05 2020-03-12 The Broad Institute, Inc. Base editing for treating hutchinson-gilford progeria syndrome
US10883084B2 (en) 2018-10-05 2021-01-05 Xenotherapeutics, Inc. Personalized cells, tissues, and organs for transplantation from a humanized, bespoke, designated-pathogen free, (non-human) donor and methods and products relating to same
JP7431837B2 (ja) 2018-10-05 2024-02-15 ゼノセラピューティクス インコーポレイテッド 異種移植製品及び異種移植方法
MX2021011426A (es) 2019-03-19 2022-03-11 Broad Inst Inc Metodos y composiciones para editar secuencias de nucleótidos.
IL297761A (en) 2020-05-08 2022-12-01 Broad Inst Inc Methods and compositions for simultaneously editing two helices of a designated double-helix nucleotide sequence

Family Cites Families (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH445129A (fr) 1964-04-29 1967-10-15 Nestle Sa Procédé pour la préparation de composés d'inclusion à poids moléculaire élevé
US3459731A (en) 1966-12-16 1969-08-05 Corn Products Co Cyclodextrin polyethers and their production
US3426011A (en) 1967-02-13 1969-02-04 Corn Products Co Cyclodextrins with anionic properties
US3453257A (en) 1967-02-13 1969-07-01 Corn Products Co Cyclodextrin with cationic properties
US3453259A (en) 1967-03-22 1969-07-01 Corn Products Co Cyclodextrin polyol ethers and their oxidation products
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
US5521063A (en) 1985-03-15 1996-05-28 Antivirals Inc. Polynucleotide reagent containing chiral subunits and methods of use
US5217866A (en) 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
EP0215942B1 (en) 1985-03-15 1995-07-12 Antivirals Inc. Polynucleotide assay reagent and method
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
US4794499A (en) 1988-02-16 1988-12-27 Ott John N Grounding device for lamp with shielded electrodes
KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
JPH07501204A (ja) 1991-06-28 1995-02-09 マサチューセッツ インスティテュート オブ テクノロジー 局所的オリゴヌクレオチド療法
EP0786522A2 (en) 1992-07-17 1997-07-30 Ribozyme Pharmaceuticals, Inc. Enzymatic RNA molecules for treatment of stenotic conditions
US5885613A (en) 1994-09-30 1999-03-23 The University Of British Columbia Bilayer stabilizing components and their use in forming programmable fusogenic liposomes
US5820873A (en) 1994-09-30 1998-10-13 The University Of British Columbia Polyethylene glycol modified ceramide lipids and liposome uses thereof
US5753613A (en) 1994-09-30 1998-05-19 Inex Pharmaceuticals Corporation Compositions for the introduction of polyanionic materials into cells
IL115849A0 (en) 1994-11-03 1996-01-31 Merz & Co Gmbh & Co Tangential filtration preparation of liposomal drugs and liposome product thereof
US6245747B1 (en) 1996-03-12 2001-06-12 The Board Of Regents Of The University Of Nebraska Targeted site specific antisense oligodeoxynucleotide delivery method
US7572582B2 (en) 1997-09-12 2009-08-11 Exiqon A/S Oligonucleotide analogues
US6794499B2 (en) 1997-09-12 2004-09-21 Exiqon A/S Oligonucleotide analogues
WO1999042091A2 (en) 1998-02-19 1999-08-26 Massachusetts Institute Of Technology Use of polycations as endosomolytic agents
US7084125B2 (en) 1999-03-18 2006-08-01 Exiqon A/S Xylo-LNA analogues
KR100782896B1 (ko) 1999-05-04 2007-12-06 엑시콘 에이/에스 Ｌ-리보-ｌｎａ 유사체
WO2001047496A1 (en) 1999-12-29 2001-07-05 Mixson A James Histidine copolymer and methods for using same
US7070807B2 (en) 1999-12-29 2006-07-04 Mixson A James Branched histidine copolymers and methods for using same
EP1446412B1 (en) 2001-09-04 2012-03-07 Exiqon A/S Novel lna compositions and uses thereof
KR100464261B1 (ko) 2002-01-24 2005-01-03 주식회사 파나진 Ｐｎａ 올리고머를 합성하기 위한 신규한 단량체 및 그의제조방법
KR20030084444A (ko) 2002-04-26 2003-11-01 주식회사 파나진 Ｐｎａ 올리고머를 합성하기 위한 신규한 단량체 및 그의제조방법
US7569575B2 (en) 2002-05-08 2009-08-04 Santaris Pharma A/S Synthesis of locked nucleic acid derivatives
US7211668B2 (en) 2003-07-28 2007-05-01 Panagene, Inc. PNA monomer and precursor
US8258109B2 (en) * 2005-10-20 2012-09-04 Isis Pharmaceuticals, Inc. Compositions and methods for modulation of LMNA expression
JP2010505741A (ja) 2006-05-10 2010-02-25 エイブイアイ バイオファーマ， インコーポレイテッド カチオン性のサブユニット間結合を有するオリゴヌクレオチドアナログ
ES2694726T3 (es) * 2007-06-29 2018-12-26 Sarepta Therapeutics, Inc. Conjugados peptídicos específicos de tejido y métodos
US20100016215A1 (en) * 2007-06-29 2010-01-21 Avi Biopharma, Inc. Compound and method for treating myotonic dystrophy
US8076476B2 (en) 2007-11-15 2011-12-13 Avi Biopharma, Inc. Synthesis of morpholino oligomers using doubly protected guanine morpholino subunits
WO2009064471A1 (en) 2007-11-15 2009-05-22 Avi Biopharma, Inc. Method of synthesis of morpholino oligomers
AU2008345033B2 (en) 2007-12-28 2014-04-03 Sarepta Therapeutics, Inc. Immunomodulatory agents and methods of use
JP5864257B2 (ja) * 2008-10-24 2016-02-17 サレプタ セラピューティクス， インコーポレイテッド Ｄｍｄのための複数のエキソンスキッピング組成物
DE102009046261B4 (de) 2009-10-30 2012-05-16 GLOBALFOUNDRIES Dresden Module One Ltd. Liability Company & Co. KG Verfahren zur Herstellung von Transistoren mit Metallgateelektrodenstrukturen mit großem ε, die vor den Drain/Source-Gebieten auf der Grundlage eines Opferkohlenstoffabstandshalters hergestellt werden
EP3199634A1 (en) * 2009-11-13 2017-08-02 Sarepta Therapeutics, Inc. Antisense antiviral compound and method for treating influenza viral infection
US8012804B1 (en) 2009-12-23 2011-09-06 Western Digital (Fremont), Llc Method and system for mounting lasers on energy assisted magnetic recording heads
AU2011257980B2 (en) 2010-05-28 2016-06-30 Sarepta Therapeutics, Inc. Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups
CN103384932A (zh) 2011-02-23 2013-11-06 日本瑞翁株式会社 二次电池用负极、二次电池、负极用浆料组合物及二次电池用负极的制造方法
KR102339196B1 (ko) 2011-05-05 2021-12-15 사렙타 쎄러퓨틱스, 인코퍼레이티드 펩타이드 올리고뉴클레오타이드 접합체
KR102271212B1 (ko) 2011-11-18 2021-07-01 사렙타 쎄러퓨틱스, 인코퍼레이티드 기능적으로-변형된 올리고뉴클레오티드 및 이의 서브유니트
HUE038369T2 (hu) 2011-12-08 2018-10-29 Sarepta Therapeutics Inc Humán LMNA-t célzó oligonukleotid-analógok

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