WO2010059706A2 - Facteurs de traduction en tant que cibles de médicament anti-vieillissement - Google Patents

Facteurs de traduction en tant que cibles de médicament anti-vieillissement Download PDF

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Publication number
WO2010059706A2
WO2010059706A2 PCT/US2009/064964 US2009064964W WO2010059706A2 WO 2010059706 A2 WO2010059706 A2 WO 2010059706A2 US 2009064964 W US2009064964 W US 2009064964W WO 2010059706 A2 WO2010059706 A2 WO 2010059706A2
Authority
WO
WIPO (PCT)
Prior art keywords
eif4a
agent
expression
nucleic acid
activity
Prior art date
Application number
PCT/US2009/064964
Other languages
English (en)
Other versions
WO2010059706A3 (fr
Inventor
Jing Huang
Rui Hao
Brett Eugene Lomenick
Nao Jonai
Simon Diep
Original Assignee
The Regents Of The University Of California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Priority to US13/129,539 priority Critical patent/US9358249B2/en
Publication of WO2010059706A2 publication Critical patent/WO2010059706A2/fr
Publication of WO2010059706A3 publication Critical patent/WO2010059706A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4703—Regulators; Modulating activity
    • G01N2333/4706—Regulators; Modulating activity stimulating, promoting or activating activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • a method of slowing the progression of age associated hair loss in a mammal comprising administering to a mammal an amount of an eIF4A inhibitor and/or a pharmaceutically acceptable salt thereof effective to slow the progression of age associated hair loss.
  • a method of slowing the progression of age associated weight loss in a mammal comprising administering to a mammal an amount of an eIF4A inhibitor and/or a pharmaceutically acceptable salt thereof effective to slow the progression of age associated weight loss.
  • this invention pertains to the discovery that resveratrol (see, Figure IA) increases lifespan (slows aging) by inhibiting translation, particularly translation mediated by eukaryotic initiation factor 4A (EIF4A). Based on this discovery it is believed that other translation inhibitors, especially inhibitors that inhibit the expression and/or activity of eIF4A can similarly increase lifespan.
  • the siRNA comprises the sequence AA(N19)TT
  • siRNA comprise approximately 30%-70% GC, and preferably comprise approximately 50% G/C.
  • the sequence of the sense siRNA strand corresponds to (N19)TT or N21 (i.e., positions 3 to 23), respectively. In the latter case, the 3' end of the sense siRNA is converted to TT.
  • the rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense strand 3' overhangs. T he antisense RNA strand is then synthesized as the complement to positions 1 to 21 of the sense strand.
  • the sense strand of the present siRNA comprises a nucleotide sequence identical to any contiguous stretch of about 19 to about 25 nucleotides in the target eukaryotic initiation factor 4 A (EIF4A) mRNA.
  • EIF4A target eukaryotic initiation factor 4 A
  • a target sequence on the target mRNA can be selected from a given cDNA sequence corresponding to the target mRNA, preferably beginning 50 to 100 nucleotides downstream (i.e., in the 3' direction) from the start codon.
  • the target sequence can, however, be located in the 5' or 3' untranslated regions, or in the region nearby the start.
  • siRNA can be expressed from a recombinant plasmid either as two separate, complementary RNA molecules, or as a single RNA molecule with two complementary regions. Selection of plasmids suitable for expressing siRNAs, methods for inserting nucleic acid sequences for expressing the siRNA into the plasmid, and methods of delivering the recombinant plasmid to the cells of interest are within the skill in the art (see, e.g., Tuschl (2002) Nat. BiotechnoL, 20: 446-448; Brummelkamp et al. (2002) Science 296: 550 553; Miyagishi et al. (2002) Nat. Biotechnol.
  • physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms.
  • Various preservatives are well known and include, for example, phenol and ascorbic acid.
  • pharmaceutically acceptable carrier(s) including a physiologically acceptable compound depends, for example, on the route of administration of the active agent(s) and on the particular physio-chemical characteristics of the active agent(s).
  • the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.
  • Opsonization inhibiting moieties suitable for modifying liposomes include water-soluble polymers with a molecular weight from about 500 to about 40,000 daltons, or from about 2,000 to about 20,000 daltons.
  • the mRNA is isolated from a given cell sample using, for example, an acid guanidinium-phenol-chloroform extraction method.
  • the mRNA is then electrophoresed to separate the mRNA species and the mRNA is transferred from the gel to a nitrocellulose membrane.
  • labeled probes are used to identify and/or quantify the target eIF4A mRNA.
  • Appropriate controls e.g. probes to housekeeping genes
  • An alternative means for determining the eIF4Aexpression level is in situ hybridization. In situ hybridization assays are well known (e.g., Angerer (1987) Meth. Enzymol 152: 649).
  • the immunoassay methods of the present invention may also be other known immunoassay methods, for example, fluorescent immunoassays using antibody conjugates or antigen conjugates of fluorescent substances such as fluorescein or rhodamine, latex agglutination with antibody-coated or antigen-coated latex particles, haemagglutination with antibody-coated or antigen-coated red blood corpuscles, and immunoassays employing an avidin-biotin or strepavidin-biotin detection systems, and the like.
  • fluorescent immunoassays using antibody conjugates or antigen conjugates of fluorescent substances such as fluorescein or rhodamine, latex agglutination with antibody-coated or antigen-coated latex particles, haemagglutination with antibody-coated or antigen-coated red blood corpuscles
  • immunoassays employing an avidin-biotin or strepavidin-biotin detection systems, and the like.
  • the assays of this invention are scored according to standard methods well known to those of skill in the art.
  • the assays of this invention are typically scored as positive where there is a difference between the activity seen with the test agent present or where the test agent has been previously applied, and the (usually negative) control.
  • the change is a statistically significant change, e.g. as determined using any statistical test suited for the data set provided (e.g. t-test, analysis of variance (ANOVA), semiparametric techniques, non-parametric techniques (e.g. Wilcoxon Mann- Whitney Test, Wilcoxon Signed Ranks Test, Sign Test, Kruskal-Wallis Test, etc.).
  • instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.
  • electronic storage media e.g., magnetic discs, tapes, cartridges, chips
  • optical media e.g., CD ROM
  • Such media may include addresses to internet sites that provide such instructional materials.
  • Example 1 EIF4A is the Molecular Target of Certain Ageing Inhibitors

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dans certains modes de réalisation, la présente invention concerne la découverte que l’inhibition de l’expression et/ou l’activité du facteur d’initiation eucaryote 4A (eIF4A) inhibe le processus de vieillissement. En conséquence, dans certains modes de réalisation, des procédés sont proposés pour inhiber/ralentir le vieillissement. Les procédés comprennent typiquement l’administration à un mammifère d’un agent qui inhibe l’expression et/ou l’activité du facteur d’initiation eucaryote 4A (eIF4A) en une quantité suffisante pour inhiber l’expression ou l’activité d’EIF4A, où l’agent n’est pas le resvératrol.
PCT/US2009/064964 2008-11-18 2009-11-18 Facteurs de traduction en tant que cibles de médicament anti-vieillissement WO2010059706A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/129,539 US9358249B2 (en) 2008-11-18 2009-11-18 Use of Pateamine A for the treatment of age-related muscle wasting

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11589408P 2008-11-18 2008-11-18
US61/115,894 2008-11-18

Publications (2)

Publication Number Publication Date
WO2010059706A2 true WO2010059706A2 (fr) 2010-05-27
WO2010059706A3 WO2010059706A3 (fr) 2010-09-16

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PCT/US2009/064964 WO2010059706A2 (fr) 2008-11-18 2009-11-18 Facteurs de traduction en tant que cibles de médicament anti-vieillissement

Country Status (2)

Country Link
US (1) US9358249B2 (fr)
WO (1) WO2010059706A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9358249B2 (en) 2008-11-18 2016-06-07 The Regents Of The University Of California Use of Pateamine A for the treatment of age-related muscle wasting
EP3077542A4 (fr) * 2013-12-05 2018-01-10 Memorial Sloan-Kettering Cancer Center Méthodes d'identification de composés antinéoplasiques

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013170257A1 (fr) * 2012-05-11 2013-11-14 Dana-Farber Cancer Institute, Inc. Traitement de cancers exprimant muc1 par des inhibiteurs d'hélicase
US10729668B2 (en) 2014-06-30 2020-08-04 The Regents Of The University Of California Ketobutyrate compounds and compositions for treating age-related symptoms and diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070196850A1 (en) * 2006-01-27 2007-08-23 University Of Washington Identification of aging genes through large-scale analysis
EP1825850A1 (fr) * 2006-02-24 2007-08-29 DSMIP Assets B.V. Utilisation du resveratrol et ses dérivés pour promouvoir le bien-être général

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010059706A2 (fr) 2008-11-18 2010-05-27 The Regents Of The University Of California Facteurs de traduction en tant que cibles de médicament anti-vieillissement
US20110319338A1 (en) 2008-12-18 2011-12-29 The Board Of Regents Of The University Of Texas System Peptides that bind eukaryotic translation initiation factor 4e

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070196850A1 (en) * 2006-01-27 2007-08-23 University Of Washington Identification of aging genes through large-scale analysis
EP1825850A1 (fr) * 2006-02-24 2007-08-29 DSMIP Assets B.V. Utilisation du resveratrol et ses dérivés pour promouvoir le bien-être général

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CURRAN, S. P. ET AL.: 'Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability.' PLOS GENETICS. vol. 3, no. 4, April 2007, pages 0479 - 0487 *
PAN, K. Z. ET AL.: 'Inhibition of mRNA translation extends life span in Caenorhabditis elegans.' AGING CELL. vol. 6, no. 1, 05 December 2006, pages 111 - 119 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9358249B2 (en) 2008-11-18 2016-06-07 The Regents Of The University Of California Use of Pateamine A for the treatment of age-related muscle wasting
EP3077542A4 (fr) * 2013-12-05 2018-01-10 Memorial Sloan-Kettering Cancer Center Méthodes d'identification de composés antinéoplasiques

Also Published As

Publication number Publication date
US9358249B2 (en) 2016-06-07
US20110288153A1 (en) 2011-11-24
WO2010059706A3 (fr) 2010-09-16

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