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WO1999011778A1 - Traitement antisense de l'hypertension pulmonaire - Google Patents

Traitement antisense de l'hypertension pulmonaire Download PDF

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Publication number
WO1999011778A1
WO1999011778A1 PCT/GB1998/002584 GB9802584W WO9911778A1 WO 1999011778 A1 WO1999011778 A1 WO 1999011778A1 GB 9802584 W GB9802584 W GB 9802584W WO 9911778 A1 WO9911778 A1 WO 9911778A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic composition
inhaler
composition according
gene
antisense
Prior art date
Application number
PCT/GB1998/002584
Other languages
English (en)
Other versions
WO1999011778B1 (fr
Inventor
Timothy Higenbottam
Keith Mccormack
Adrian Smith
Original Assignee
University Of Sheffield
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 University Of Sheffield filed Critical University Of Sheffield
Priority to CA002302167A priority Critical patent/CA2302167A1/fr
Priority to EP98940410A priority patent/EP1009822A1/fr
Priority to JP2000508789A priority patent/JP2001515011A/ja
Priority to AU88741/98A priority patent/AU8874198A/en
Publication of WO1999011778A1 publication Critical patent/WO1999011778A1/fr
Publication of WO1999011778B1 publication Critical patent/WO1999011778B1/fr

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Classifications

    • 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
    • C12N15/1136—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 against growth factors, growth regulators, cytokines, lymphokines or hormones
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to a method and means to treat, but not exclusively, pulmonary hypertension by functionally suppressing the product of the ET-1 gene which encodes a vasoconstrictor peptide the expression of which is correlated mainly with this disorder.
  • Pulmonary Hypertension is a disorder in which the blood pressure in the pulmonary (lung) arteries is abnormally high in the absence of other diseases of the heart or lungs. PH is considered to be present when the mean pulmonary arterial pressure is greater than 25mmHg at rest or 30mmHg during activity. The normal mean pulmonary - artery pressure is approximately 14mmHg at rest. PH is classified according to whether the disorder is primary or secondary PH.
  • PPH Primary PH
  • SPH Secondary Pulmonary Hypertension
  • the successful clinical treatments include the continuous intravenous administration of prostacyclin (PGI 2 ) and inhaled nitric oxide (NO), for severe disease; for milder degrees of illness, anticoagulants and calcium channel blockers can be used to lessen symptoms and improve survival.
  • PKI 2 prostacyclin
  • NO inhaled nitric oxide
  • ET-1 endothelin-1
  • BQ-123 has been shown to antagonise the activity of ET-1 receptors and relieve pulmonary hypertension resulting from congestive heart failure.
  • m NA to ET-1 was shown to decrease as a consequence of long term BQ-123 treatment.
  • a recent strategy to interfere with the expression of a gene is that of antisense technology.
  • this strategy involves the use of a DNA or RNA molecule that is complementary to a region of a selected gene and is able to hybridise (bind) under physiological conditions to the targeted nucleic acid to prevent either transcription of the gene or translation of the mRNA encoded by the gene.
  • the antisense molecule is often a short oligodeoxynucleotide (ODN).
  • the molecule may be an oligodeoxyribonucleotide, or a modified oligodeoxynucleotide, or a modified oligodeoxyribonucleotide; each of which are able to hybridised to a selected part of a gene, or mRNA, under physiological conditions.
  • the modifications to oligodeoxynucleotides will be apparent to one skilled in the art.
  • the exact region of the nucleotide sequence of the gene to which the antisense molecule is designed can be empirically determined. However it is common practice to design oligodeoxynucleotides to the 5' region of the gene (to interfere with transcription initiation) or the mRNA (to interfere with translation).
  • the region of the gene to which the antisense molecule is directed is determined by the efficiency with which the antisense molecule suppresses the gene of interest. Contrary to the above this may be the 3' region and is determined experimentally.
  • the length of the ODN also has to be determined experimentally. Typically ODNs are 20- 30 nucleotides in length but may be much longer.
  • nitric oxide a known vasodilator
  • the very short pulse of nitric oxide is provided at the start of the inhalation, such that the resultant bolus of nitric oxide mixture inhaled by the patient has a nitric oxide concentration high enough to have the desired therapeutic effect, even if admixed with some additional air, but is of such short duration (both in time and as a result, in physical amount) that, pushed by the following much larger volume of plain, and therefore nitric oxide - free, air/oxygen, it reaches deeper into the lungs, where it both acts on the small pulmonary arteries and is taken up into the capillaries,
  • the invention therein described is a small (pocket-sized) hand held treatment apparatus that utilises the "spike” principle.
  • the invention comprises a conventional nebuliser (having a reservoir in which is stored the medicament to be administered) driven by some suitable pressurised gas from a valved cylinder so as to deliver a medicament into a tube through which the patient is breathing (by mouth) normal air, the gas cylinder valve being controlled by a suitably programmed computing device that is fed data describing the pressure within the breathing tube and so is able to open and close the valve at, and for, a time such as to drive the nebuliser to deliver (to the tube and thence to the patient's lungs) a required pulse of medicament at any selected point within the patient's respiratory cycle.
  • the idea of this is simply to ensure that a high concentration of the medicament reaches and affects the target area, and the target area alone, rather than having the whole of the lungs subjected to it.
  • HsET132 CTC AAA GCG ATC CTT CAG CC
  • HsET868 ATG TGC TCG GTT GTG GGT CA
  • At least one rat ET-1 antisense oligonucleotides as represented in Table 2.
  • a method for determining the efficacy of antisense ET-1 molecules comprising exposing a known hypersensitive animal model system to antisense ET-1 for studying molecules and observing the effects of same on pulmonary hypertension.
  • said therapeutic treatment is based on antisense therapy.
  • said antisense therapy is based on the ET-1 sequence and more preferably still those sequences represented in Table 1 and/or Table 2, and/or sequences homologous or analogous thereto, wherein said homology is at least 50%, ideally 75% and preferably at least
  • an antisense molecule adapted to hybridise to the transcriptional promoter region of the ET-1 gene to inhibit transcription of said gene.
  • an antisense molecule adapted to hybridise to splice junctions between exons and introns of prepromessenger RNA encoding the ET-1 protein.
  • ET-1 gene can be inhibited by interfering with the splicing of introns from the pre mRNA of ET-1 to prevent the formation of a mature, translatable mRNA.
  • an inhaler comprising means for administering the aforedescribed antisense molecules encoding ET-1 nucleic acid wherein said administration is via a spike or pulse and preferably only during inhalation by the patient.
  • said inhaler is disposable and adapted to receive a cartridge containing antisense molecules encoding the ET-1 nucleic acid composition.
  • the invention hereindescribed therefore provides a means of controlling pulmonary hypertension using aerosolised antisense molecules to the ET-1 gene, and/or mRNA, to inhibit the vasoconstrictor activity of ..the ET-1 peptide.
  • the delivery of the antisense molecule makes use of an inhaler that functions during patient inhalation to drive the therapeutic composition deep into the lungs to deliver the antisense molecule to the endothelial cells that line the arterioles of the lungs and thereby target those blood vessels that result in pulmonary hypertension.
  • Figure 1 represents the genomic DNA sequence of human ET-1.
  • HsET132 CTC AAA GCG ATC CTT CAG CC
  • HsET318 AGC TCA GCG CCT AAG ACT GC HsET438 TGG CAG AAG TAG ACA CAC TC
  • HsET868 ATG TGC TCG GTT GTG GGT CA
  • Regions of loose secondary structure were defined as sequences of >8 adjacent bases in the mRNA sequence for which there were no predicted intra-molecule Watson-Crick base pairing determined using the Wisconsin Genetics Computer Group software package RNAFOLD.
  • the mRNA sequence was then imported into the 'primer' package on the Sheffield 'biocomp service' and complemented (G for C, T for A etc.).
  • the regions of loose predicted secondary structure were sought and the oligo criteria were selected.
  • the 3' most bases were aligned with the region of no predicted secondary structure. If the sequence highlighted met all set criteria the sequence and position was recorded. If the sequence failed to reach the criteria the highlighted 20 base sequence was shifted 5' until either a sequence was identified meeting the criteria or the ⁇ 5 bases remained within the region of loose predicted secondary structure at which point the region was rejected.
  • the sequence with the most central homology to that of the loose predicted secondary structure was selected.
  • ET-1 antisense material Current data relating to the efficacy of ET-1 antisense material is in vitro cell culture work. Selected antisense molecules are transfected into cells in culture and the level of ET-1 protein determined by western blotting and/or immunofluoresence using ET-1 antisera. A down regulation of ET-1 protein results when selected antisense molecules are used. Currently we are unable to identify the mechanism by which ET-1 protein is down regulated (ie destabilisation of mRNA, inhibition of translation). Further work will optimise conditions with respect to providing a suitable composition for use in in vivo studies.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plant Pathology (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une méthode de traitement de l'hypertension pulmonaire par une thérapie antisens faisant appel à des molécules antisens dérivées de ET-1 administrées dans les poumons comme une impulsion/pointe dans un inhalateur.
PCT/GB1998/002584 1997-09-02 1998-09-02 Traitement antisense de l'hypertension pulmonaire WO1999011778A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002302167A CA2302167A1 (fr) 1997-09-02 1998-09-02 Traitement antisense de l'hypertension pulmonaire
EP98940410A EP1009822A1 (fr) 1997-09-02 1998-09-02 Traitement antisense de l'hypertension pulmonaire
JP2000508789A JP2001515011A (ja) 1997-09-02 1998-09-02 肺高血圧症のアンチセンス治療
AU88741/98A AU8874198A (en) 1997-09-02 1998-09-02 Antisense treatment of pulmonary hypertension

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9718487.3 1997-09-02
GBGB9718487.3A GB9718487D0 (en) 1997-09-02 1997-09-02 Pulmonary hypertension

Publications (2)

Publication Number Publication Date
WO1999011778A1 true WO1999011778A1 (fr) 1999-03-11
WO1999011778B1 WO1999011778B1 (fr) 1999-04-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/002584 WO1999011778A1 (fr) 1997-09-02 1998-09-02 Traitement antisense de l'hypertension pulmonaire

Country Status (6)

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EP (1) EP1009822A1 (fr)
JP (1) JP2001515011A (fr)
AU (1) AU8874198A (fr)
CA (1) CA2302167A1 (fr)
GB (1) GB9718487D0 (fr)
WO (1) WO1999011778A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087343A (en) * 1998-09-14 2000-07-11 University Of Florida Antisense oligonucleotides targeted to β-1 adrenoceptor and methods of use
WO2000055314A3 (fr) * 1999-03-18 2001-02-22 United Therapeutics Corp Inhibiteurs de synthese de l'endotheline-1
EP1080225A1 (fr) * 1998-05-21 2001-03-07 Isis Pharmaceuticals, Inc. Compositions et methodes d'administration aux poumons d'acides nucleiques
EP1086116A1 (fr) * 1998-05-21 2001-03-28 Isis Pharmaceuticals, Inc. Compositions destinees a l'administration pulmonaire d'acides nucleiques et procedes
WO2002024747A3 (fr) * 2000-09-19 2003-07-31 Epidauros Biotechnologie Ag Polymorphismes dans des genes humains de regulateurs cardio-vasculaires et leur utilisation dans des applications diagnostiques et therapeutiques
WO2016083624A1 (fr) * 2014-11-28 2016-06-02 Silence Therapeutics Gmbh Moyens d'inhibition de l'expression d'edn1

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027664A1 (fr) * 1993-06-02 1994-12-08 British Technology Group Limited Dispositif d'inhalation therapeutique
GB2283179A (en) * 1993-10-12 1995-05-03 Timothy William Higenbottam Apparatus for nitric oxide treatment
WO1996040162A1 (fr) * 1995-06-07 1996-12-19 East Carolina University Procede de traitement de maladies pulmonaires au moyen d'oligonucleotides antisens
GB2320900A (en) * 1997-01-07 1998-07-08 Univ Sheffield Inhalers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027664A1 (fr) * 1993-06-02 1994-12-08 British Technology Group Limited Dispositif d'inhalation therapeutique
GB2283179A (en) * 1993-10-12 1995-05-03 Timothy William Higenbottam Apparatus for nitric oxide treatment
WO1996040162A1 (fr) * 1995-06-07 1996-12-19 East Carolina University Procede de traitement de maladies pulmonaires au moyen d'oligonucleotides antisens
GB2320900A (en) * 1997-01-07 1998-07-08 Univ Sheffield Inhalers

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BUTT A.Y. ET AL: "Pathophysiological basis of the treatment of pulmonary hypertension.", EUROPEAN RESPIRATORY REVIEW, (1995) 5/29 (248-251)., XP002092834 *
SAKAI S ET AL: "Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of an endothelin receptor antagonist : Increased expression of endothelin -1 messenger ribonucleic acid and endothelin -1-like immunoreactivity in the lung in congestive heart failure in rats.", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, (1996 NOV 15) 28 (6) 1580-8., XP002092833 *
STELZNER, T. ET AL.: "Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension", AMER. J. PHYSIOL., vol. 262, May 1992 (1992-05-01), pages L614 - L620, XP002092835 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1080225A1 (fr) * 1998-05-21 2001-03-07 Isis Pharmaceuticals, Inc. Compositions et methodes d'administration aux poumons d'acides nucleiques
EP1086116A1 (fr) * 1998-05-21 2001-03-28 Isis Pharmaceuticals, Inc. Compositions destinees a l'administration pulmonaire d'acides nucleiques et procedes
EP1080225A4 (fr) * 1998-05-21 2004-02-04 Isis Pharmaceuticals Inc Compositions et methodes d'administration aux poumons d'acides nucleiques
EP1086116A4 (fr) * 1998-05-21 2004-03-17 Isis Pharmaceuticals Inc Compositions destinees a l'administration pulmonaire d'acides nucleiques et procedes
US6087343A (en) * 1998-09-14 2000-07-11 University Of Florida Antisense oligonucleotides targeted to β-1 adrenoceptor and methods of use
WO2000055314A3 (fr) * 1999-03-18 2001-02-22 United Therapeutics Corp Inhibiteurs de synthese de l'endotheline-1
US7423141B2 (en) 1999-03-18 2008-09-09 William Harvey Research Ltd. Inhibitors of endothelin-1 synthesis
WO2002024747A3 (fr) * 2000-09-19 2003-07-31 Epidauros Biotechnologie Ag Polymorphismes dans des genes humains de regulateurs cardio-vasculaires et leur utilisation dans des applications diagnostiques et therapeutiques
WO2016083624A1 (fr) * 2014-11-28 2016-06-02 Silence Therapeutics Gmbh Moyens d'inhibition de l'expression d'edn1

Also Published As

Publication number Publication date
AU8874198A (en) 1999-03-22
WO1999011778B1 (fr) 1999-04-15
GB9718487D0 (en) 1997-11-05
EP1009822A1 (fr) 2000-06-21
JP2001515011A (ja) 2001-09-18
CA2302167A1 (fr) 1999-03-11

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