WO2002038781A1 - Utilisation de facteurs de transcription specifiques du coeur du type helice-boucle-helice de base pour le traitement de l'insuffisance cardiaque - Google Patents

Utilisation de facteurs de transcription specifiques du coeur du type helice-boucle-helice de base pour le traitement de l'insuffisance cardiaque Download PDF

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Publication number
WO2002038781A1
WO2002038781A1 PCT/DE2001/004132 DE0104132W WO0238781A1 WO 2002038781 A1 WO2002038781 A1 WO 2002038781A1 DE 0104132 W DE0104132 W DE 0104132W WO 0238781 A1 WO0238781 A1 WO 0238781A1
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WO
WIPO (PCT)
Prior art keywords
heart
helix
transcription factors
loop
power failure
Prior art date
Application number
PCT/DE2001/004132
Other languages
German (de)
English (en)
Inventor
Ingo Morano
Original Assignee
Max-Delbrück-Centrum für Molekulare Medizin
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 Max-Delbrück-Centrum für Molekulare Medizin filed Critical Max-Delbrück-Centrum für Molekulare Medizin
Priority to AU2002221542A priority Critical patent/AU2002221542A1/en
Publication of WO2002038781A1 publication Critical patent/WO2002038781A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/022—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus

Definitions

  • the invention relates to the use of heart-specific transcription factors of the basic helix-loop-helix type for the treatment of heart failure. Areas of application of the invention are medicine and the pharmaceutical industry
  • Basic helix-loop-helix (bHLH) transcription factors of the MyoD type are important regulators of skeletal muscle development and increase the expression of muscle-specific genes by binding to certain response elements in the promoter region of the target genes, the so-called E-box elements.
  • heart-specific bHLH was discovered in the heart, which, like MyoD, belongs to type B of the bHLH transcription factors. They control heart development and maturation of the cardiac system in the left and right nentricles and have been referred to as eHA ⁇ D and dHA ⁇ D (Srivastava et al. (1995), Science 270: 1995-1999).
  • the atrial light myosin chain (ALC-1), which is expressed as compensation in the overloaded human ventricle, increases the contractility of the heart.
  • the promoter region of the ALC-1 gene has several E-box elements. These E-box elements alone are sufficient to activate the ALC-1 expression.
  • the HA ⁇ D transcription factors also bind to E-box elements. We found evidence of regulation of ALC-1 expression in the human heart by both HA ⁇ D transcription factors in the hypertrophied human ventricle: The higher the ALC-1 expression, the higher the eHA ⁇ D and dHA ⁇ D mR ⁇ A expression (Ritter et al. (1999 ) J. Cell. Biochem. 24: 551-561).
  • the terminally insufficient human heart is characterized by insufficient contractility and increased apoptosis of the cardiomyocytes. It also expresses little or no ALC-1 levels in the nentricle.
  • the invention is therefore based on the object of developing an agent which restores the contractility of the heart and inhibits the apoptosis of the cardiomyocytes.
  • the invention is implemented according to the claims.
  • the underlying idea is based on the therapeutic increase in HA ⁇ D expression in insufficient human hearts. This has a positive influence on two pathologically relevant phenomena of heart failure. 1.
  • HAND transcription factors increase ALC-1 expression in the heart. In this way, an endogenous compensation mechanism is mimicked, which normally increases the contractility of the overloaded human heart and which no longer exists or only exists to a limited extent in the failing heart.
  • HAND transcription factors inhibit apopotosis.
  • the gradual loss of functional heart muscle cells in the insufficient heart can be stopped by therapeutic overexpression of the hand, thereby stabilizing the morphology of the heart as an organ.
  • HAND transcription factors are therefore able to have a positive effect on terminal heart failure at several levels, and thereby improve the symptoms of heart failure at the molecular, cellular and organ level.
  • Therapeutic vehicles that are suitable for highly efficient transfection of the heart with HAND are in particular all viral vectors.
  • Replication-deficient adenoviral vectors which are commercially available in many forms, are particularly suitable as HAND vehicles.
  • the ectopic expression of the HAND transcription factors for the therapy of the failing human heart has several advantages over other forms of gene therapy.
  • the dual effect of the HAND factors on apoptosis and contractility improves organ function.
  • transcription factors act in the smallest amounts, so that the amount of vehicles required for gene therapy - that is, the number of adenoviruses - can be kept extremely low. In this way, for example, immunological side effects of virus therapy can be largely suppressed.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne l'utilisation de facteurs de transcription spécifiques du coeur du type hélice-boucle-hélice de base pour le traitement de l'insuffisance cardiaque. Les domaines d'application de l'invention sont la médecine et l'industrie pharmaceutique. L'objectif de l'invention est de développer un agent qui rétablit la contractilité du coeur et inhibe l'apoptose des cardiomiocytes. L'agent selon l'invention, qui est destiné au traitement de l'insuffisance cardiaque, se caractérise en ce qu'il contient des constructions qui sont adaptées pour la transfection du coeur avec des facteurs de transcription du type hélice-boucle-hélice de base. Des facteurs de transcription préférés sont les facteurs eHAND et dHAND.
PCT/DE2001/004132 2000-11-07 2001-11-07 Utilisation de facteurs de transcription specifiques du coeur du type helice-boucle-helice de base pour le traitement de l'insuffisance cardiaque WO2002038781A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002221542A AU2002221542A1 (en) 2000-11-07 2001-11-07 Use of heart-specific transcription factors of the basic helix-loop-helix type for treating cardiac power failure

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10055157.2 2000-11-07
DE10055157 2000-11-07

Publications (1)

Publication Number Publication Date
WO2002038781A1 true WO2002038781A1 (fr) 2002-05-16

Family

ID=7662441

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2001/004132 WO2002038781A1 (fr) 2000-11-07 2001-11-07 Utilisation de facteurs de transcription specifiques du coeur du type helice-boucle-helice de base pour le traitement de l'insuffisance cardiaque

Country Status (3)

Country Link
AU (1) AU2002221542A1 (fr)
DE (1) DE10154224A1 (fr)
WO (1) WO2002038781A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999028469A1 (fr) * 1997-12-04 1999-06-10 Genzyme Corporation Compositions et procedes induisant l'expression genique
WO2001012126A2 (fr) * 1999-08-13 2001-02-22 President And Fellows Of Harvard College Regeneration de cardiomyocytes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999028469A1 (fr) * 1997-12-04 1999-06-10 Genzyme Corporation Compositions et procedes induisant l'expression genique
WO2001012126A2 (fr) * 1999-08-13 2001-02-22 President And Fellows Of Harvard College Regeneration de cardiomyocytes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HOWARD MARTHE ET AL: "Expression of HAND gene products may be sufficient for the differentiation of avian neural crest-derived cells into catecholaminergic neurons in culture.", DEVELOPMENTAL BIOLOGY, vol. 215, no. 1, 1 November 1999 (1999-11-01), pages 62 - 77, XP001062855, ISSN: 0012-1606 *
SRIVASTAVA D: "HAND proteins: molecular mediators of cardiac development and congenital heart disease.", TRENDS IN CARDIOVASCULAR MEDICINE, (1999 JAN-FEB) 9 (1-2) 11-8. REF: 42, XP001062877 *

Also Published As

Publication number Publication date
DE10154224A1 (de) 2002-06-20
AU2002221542A1 (en) 2002-05-21

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