AR097738A1 - METHODS TO TREAT OR PREVENT DISEASES ASSOCIATED WITH TRANSTIRETINE (TTR) - Google Patents

METHODS TO TREAT OR PREVENT DISEASES ASSOCIATED WITH TRANSTIRETINE (TTR)

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Publication number
AR097738A1
AR097738A1 ARP140103519A ARP140103519A AR097738A1 AR 097738 A1 AR097738 A1 AR 097738A1 AR P140103519 A ARP140103519 A AR P140103519A AR P140103519 A ARP140103519 A AR P140103519A AR 097738 A1 AR097738 A1 AR 097738A1
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AR
Argentina
Prior art keywords
ttr
nucleotides
yyy
zzz
xxx
Prior art date
Application number
ARP140103519A
Other languages
Spanish (es)
Inventor
G Rajeev Kallanthottathil
Zimmermann Trady
Manoharan Muthiah
Maier Martin
Kuchimanchi Satyanarayana
Charisse Klaus
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Alnylam Pharmaceuticals Inc
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Application filed by Alnylam Pharmaceuticals Inc filed Critical Alnylam Pharmaceuticals Inc
Publication of AR097738A1 publication Critical patent/AR097738A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3515—Lipophilic moiety, e.g. cholesterol

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Métodos para tratar o prevenir enfermedades asociadas con la transtiretina (TTR) usando agentes de ARNi, por ejemplo, agentes de ARNi de doble hebra, que se dirigen contra el gen de transtiretina (TTR). Reivindicación 1: Un método para tratar o prevenir una enfermedad relacionada con la TTR en un sujeto, caracterizado porque comprende administrar a dicho sujeto un agente de ARNi a una dosis de aproximadamente 7,5 mg/kg, por día durante cinco días, seguido por una dosis de aproximadamente 7,5 mg/kg por semana durante aproximadamente cinco semanas, en donde el agente de ARNi es un agente de ARNi de doble hebra, que comprende una cadena orientada en el sentido del marco de lectura que es complementaria de una hebra antisentido, en donde dicha hebra antisentido comprende una región que es la parte complementaria de un ARNm que codifica transtiretina (TTR), en donde cada cadena tiene entre aproximadamente 14 y aproximadamente 30 nucleótidos, en donde dicho agente de ARNi de doble hebra está representado por la fórmula: hebra sentido: 5 nₚ-Na-(XXX)ⁱ-Nb-YYY-Nb-(ZZZ)ʲ-Na-nq 3 hebra antisentido: 3 nₚ-Na-(XXX)ₖ-Nb-YYY-Nb-(ZZZ)ₗ-Na-nq 5 en donde: i, j, k y I son cada uno de manera independiente 0 ó 1; p, p, q y q son cada uno de manera independiente 0 - 6; cada Na y Na representa de manera independiente una secuencia de oligonucleótidos que comprende 0 - 25 nucleótidos que están modificados o no modificados o combinaciones de los mismos, donde cada secuencia comprende al menos dos nucleótidos modificados de manera diferente; cada Nb y Nb representa de manera independiente una secuencia de oligonucleótidos que comprende 0 - 10 nucleótidos que están modificados o no modificados o combinaciones de los mismos; cada nₚ, nₚ, nq y nq representa de manera independiente un nucleótido saliente; XXX, YYY, ZZZ, XXX, YYY, y ZZZ representan cada uno de manera independiente un motivo de tres modificaciones idénticas en tres nucleótidos consecutivos; las modificaciones de Nb difieren de la modificación de Y; y las modificaciones de Nb difieren de la modificación de Y; y en donde la hebra sentido se conjuga a por lo menos un ligando, con lo que se trata o previene dicha enfermedad asociada con TTR en dicho sujeto.Methods for treating or preventing diseases associated with transthyretin (TTR) using RNAi agents, for example, double-stranded RNAi agents, which are directed against the transthyretin gene (TTR). Claim 1: A method of treating or preventing a TTR-related disease in a subject, characterized in that it comprises administering to said subject an RNAi agent at a dose of approximately 7.5 mg / kg, per day for five days, followed by a dose of approximately 7.5 mg / kg per week for approximately five weeks, wherein the RNAi agent is a double stranded RNAi agent, which comprises a chain oriented in the sense of the reading frame that is complementary to a strand antisense, wherein said antisense strand comprises a region that is the complementary part of an mRNA encoding transthyretin (TTR), wherein each chain has between about 14 and about 30 nucleotides, wherein said double stranded RNAi agent is represented by the formula: strand sense: 5 nₚ-Na- (XXX) ⁱ-Nb-YYY-Nb- (ZZZ) ʲ-Na-nq 3 antisense strand: 3 nₚ-Na- (XXX) ₖ-Nb-YYY-Nb- (ZZZ) ₗ-Na-nq 5 where: i, j, k and I are each of ma nera independent 0 or 1; p, p, q and q are each independently 0-6; each Na and Na independently represents an oligonucleotide sequence comprising 0-25 nucleotides that are modified or unmodified or combinations thereof, where each sequence comprises at least two differently modified nucleotides; each Nb and Nb independently represents an oligonucleotide sequence comprising 0-10 nucleotides that are modified or unmodified or combinations thereof; each nₚ, nₚ, nq and nq independently represents an outgoing nucleotide; XXX, YYY, ZZZ, XXX, YYY, and ZZZ each independently represent a reason for three identical modifications in three consecutive nucleotides; the modifications of Nb differ from the modification of Y; and the modifications of Nb differ from the modification of Y; and wherein the sense strand is conjugated to at least one ligand, with which said disease associated with TTR is treated or prevented in said subject.

ARP140103519A 2013-09-23 2014-09-23 METHODS TO TREAT OR PREVENT DISEASES ASSOCIATED WITH TRANSTIRETINE (TTR) AR097738A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US201361881257P 2013-09-23 2013-09-23

Publications (1)

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AR097738A1 true AR097738A1 (en) 2016-04-13

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Country Status (3)

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AR (1) AR097738A1 (en)
TW (1) TW201610151A (en)
WO (1) WO2015042564A1 (en)

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WO2015042564A1 (en) 2015-03-26
TW201610151A (en) 2016-03-16
WO2015042564A8 (en) 2015-05-28

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