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WO1993007265A1 - Traitement de la fibrose cystique - Google Patents

Traitement de la fibrose cystique Download PDF

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Publication number
WO1993007265A1
WO1993007265A1 PCT/US1992/008346 US9208346W WO9307265A1 WO 1993007265 A1 WO1993007265 A1 WO 1993007265A1 US 9208346 W US9208346 W US 9208346W WO 9307265 A1 WO9307265 A1 WO 9307265A1
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WO
WIPO (PCT)
Prior art keywords
camp
compound
phosphodiesterase inhibitor
methylxanthine
cell population
Prior art date
Application number
PCT/US1992/008346
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English (en)
Inventor
Francis S. Collins
Mitchell L. Drumm
David C. Dawson
Daniel W. Wilkinson
Original Assignee
The Regents Of The University Of Michigan
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 Michigan filed Critical The Regents Of The University Of Michigan
Publication of WO1993007265A1 publication Critical patent/WO1993007265A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4712—Cystic fibrosis
    • 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 present invention relates generally to the treatment of chloride secretion insufficiencies caused by defects in cystic fibrosis transmembrane conductance regulator (CFTR) with compounds which increase or supplement cyclic AMP (cAMP) levels and, more specifically, to the treatment of cystic fibrosis (CF) with therapeutically effective amounts of phosphodiesterase inhibitors such as methyixanthines.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • cAMP cyclic AMP
  • Cystic fibrosis is the most common lethal autosomal recessive disease among Caucasians, affecting nearly 1 in 2500 newborns. Boat et al., Metabolic Basis of Inherited
  • CF cystic fibrosis transmembrane conductance regulator
  • the present invention provides a method of treatment of chloride secretion insufficiencies caused by CFTR defects generally comprising the administration to the patient of a therapeutically effective amount of a compound, or pharmaceutically acceptable form thereof, which increases or supplements cyclic AMP (cAMP) levels.
  • the method of the invention thus further provides a method of treatment of CF though the administration of therapeutically effective amounts of such compounds, which include phosphodiesterase inhibitors, cAMP and its analogs and ⁇ adrenergic receptor agonists.
  • the present invention also provides a method for in vitro dosage determination and screening for CF patient-responsiveness to treatment with the aforementioned compounds.
  • FIG. 1 A shows membrane currents at a holding potential of -60 mV from oocytes injected with either wild type or ⁇ F508 cRNA-injected and uninjected oocytes.
  • Figure 1B is a dose response curve comparing the effects of increasing IBMX concentrations on wild type and ⁇ F508 cRNA-injected oocytes.
  • Figure 2A is a bar graph comparing the maximal currents elicited in oocytes expressing each CFTR variant studied.
  • Figure 2B is a dose response curve showing activated currents (expressed as % activation) for five CFTR variants plotted against the concentration of IBMX in the bath.
  • Figure 3A shows representative l-V plots obtained at maximal activation in oocytes injected with wild type cRNA.
  • Figure 3B shows representative i-V plots obtained at maximal activation in oocytes injected with ⁇ F508 cRNA.
  • Figure 4 is a Table comparing CF patient genotype with clinical phenotype. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • Cystic fibrosis a genetic disease associated with a defect in Cl transport, is caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR), which has been proposed to function as a Cl channel.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • NBF1 first nucleotide binding fold
  • Sensitivity of the CFTR mutants to a phosphodiesterase inhibitor (IBMX) and forskolin inversely correlated with the severity of cystic fibrosis in patients carrying the mutations, i.e., mutations associated with severe disease being less sensitive than those associated with mild disease.
  • Even the least sensitive mutants ( ⁇ F508, G551 ) could be activated to a Cl conductance level approaching that of wild type by increasing the concentration of phosphodiesterase inhibitor (IBMX) and forskolin.
  • the present invention thus comprises a method of treatment of cAMP-activatable chloride secretion insufficiencies associated wfth CFTR defects, such as cystic fibrosis, by the administration to the patient of therapeutically effective amounts of a compound, or pharmaceuticaily acceptable form thereof, which increases or supplements cAMP levels.
  • a compound, or pharmaceuticaily acceptable form thereof which increases or supplements cAMP levels.
  • an increase or supplementation of cAMP levels can be achieved through an increase in cAMP production, inhibition of its breakdown or the administration of supplemental cAMP or analogs thereof.
  • An increase in production, decrease in breakdown or supplementation of cAMP with cAMP or its analogs are hereinafter collectively referred to as "elevation of cAMP levels.”
  • the present invention also provides a method for determining appropriate dosages and relative efficacy of compounds for specific CFTR defects and individual patients, and allows the design and monitoring of appropriate treatments in accordance with the invention.
  • the levels of response for different CFTR mutations may vary with a specific compound.
  • CF patient tissues or cell populations carrying the defect of interest can thus be tested, for example in culture, to assist in determining which type and dosage of compound or combination of compounds are most beneficial for carriers of that mutation or the individual patient.
  • Preferred compounds for administration in the practice of the method of the invention which elevate cAMP levels include phosphodiesterase inhibitors which increase cAMP levels by inhibiting cAMP breakdown.
  • Supplemental cAMP and analogs thereof or ⁇ adrenergic receptor agonists, such as isoproterenol and albuterol, can also be employed in the practice of the invention.
  • Preferred phosphodiesterase inhibitors which increase cAMP levels include nonspecific inhibitors such as alkylxanthines and cAMP-specific inhibitors such as Rolipram (Shearing AG).
  • a review of phosphodiesterase inhibitors and their selection is presented by Nicholson et al., Trends Pharmacol. Sciences 12:19 (1991) and Beavo et al., Trends Pharmacol. Sciences 11:150 (1990), which are incorporated herein by reference.
  • Preferred alkylxanthines include the methylxanthines, such as 3-isobutyl-1 -methylxanthine (IBMX) and 1 , 3-dimethylxanthine (theophyliine) and other xanthines such as papaverine, pentoxifiliine and caffeine.
  • Methylxanthines such as IBMX are most preferred.
  • the aforementioned compounds may be administered alone, they are preferably administered as part of a pharmaceutical formulation.
  • Such formulations can include pharmaceutically acceptable carriers known to those skilled in the art, as well as other therapeutic agents.
  • the compounds of the method of the present invention can be administered in various pharmaceutically acceptable forms, e.g., such as pharmaceutically acceptable salts thereof.
  • Appropriate dosages of the compounds and formulations administered in accordance with the invention will depend on the type of CFTR mutation and severity of the condition being treated and may also vary from patient to patient. Determining an acceptable or optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the dose and treatment of the present invention. For a dose to be "therapeutically effective,” it must have the desired effect, i.e., an elevation in cAMP levels as defined herein, resulting in increased Cl secretion by the cell population being or to be treated with the dosage. An optimal dose will be one which, when administered to the patient carrying a CFTR defect, results in Cl secretion at or near wild type CFTR levels.
  • Administration may be by any suitable route including oral, nasal, topical (including buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous and intradermal), vaginal or rectal, with oral and nasal administration being preferred.
  • the formulations thus include those suitable for administration through such routes. It will be appreciated that the preferred route may vary with, for example, the condition and age of the patient.
  • the formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and may be prepared and administered by any methods well known in the art of pharmacy, including liposomal delivery systems.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, as a powder or granules, or as a solution, suspension or emulsion.
  • Formulations suitable for oral topical administration further include lozenges, pastilles, mouthwashes and inhalation mists administered in a suitable base or liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the compound to be administered and a pharmaceutically acceptable carrier or in a transdermal patch.
  • Formulations suitable for nasal administration wherein the carrier is a solid include powders of a particle size, for example about 20 to 500 microns, which can be administered by rapid inhalation through the nasal passage.
  • Suitable formulations wherein the carrier is a liquid can be administered, for example, as a nasal spray or drops.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic wfth the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit or mufti-dose containers, for example, sealed ampules and vials, and may be lyophilized, requiring only the addition of the sterile liquid carrier such as water for injections immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray; formulations for rectal administration may be presented as a suppository with a suitable base.
  • formulations used in the methods of this invention may include other agents conventional in the art having regard to the type of formulation in question.
  • EXAMPLE 1 Activation of Cl Current by Phosphodiesterase Inhibitor.
  • Ovarian lobes were removed from anesthetized frogs via a small abdominal incision. Stage V oocytes were separated from follicular membranes by exposure to collagenase (Gibco) and gentle dissection, and were injected with 10-15 ng of cRNA. Three to 12 days after injection, oocytes were assayed for activatable membrane currents by means of two electrode voltage clamps. Outward membrane current was defined as positive. During these experiments, the oocytes were continuously perfused with amphibian Ringers containing 100 mM Na; 106 mM Cl; 2.0 mM K; 5 mM HEPES; 1.8 mM Ca and 1.0 mM Mg 100 at pH 7.4. Where indicated, Cl was replaced by aspartate. Membrane currents (I M ) were recorded from Xenopus oocytes at a holding potential
  • FIG. 1A Shown in Figure 1A are results from oocytes harvested from the same frog on the dame day and injected 3 days previously with cRNA transcribed from wild type or ⁇ F508 CFTR and an uninjected oocyte control. Shown in Figure 1A is the prior to stimulation, during exposure to a stimulatory cocktail containing 200 ⁇ M 8-chlorophenylthio cAMP (8-cpt cAMP), 10 ⁇ M forskolin and 1 mM IBMX, and during washout of the cocktail.
  • a stimulatory cocktail containing 200 ⁇ M 8-chlorophenylthio cAMP (8-cpt cAMP), 10 ⁇ M forskolin and 1 mM IBMX, and during washout of the cocktail.
  • Oocytes were harvested from the same frog as described in Example 1 A, but about 2 weeks later, and injected with wild type and ⁇ F508 cRNA. Three days after injection, the oocytes were exposed to a stimulation cocktail containing 10 ⁇ M forskolin and, successively, 1 mM and 5 mM IBMX. 8-cpt cAMP was eliminated from the cocktail on the basis of other experiments which showed that it had little effect alone or in combination with forskolin and IBMX. The difference in the currents seen with 1 mM IBMX in Figure 1 A and 1 B is typical of the variability seen in expression in oocytes taken from the same frog at different times. As shown in Figure 1 B, raising the concentration of IBMX to 5 mM elevated the current in the ⁇ F508-injected oocyte to a level comparable to wild type, whereas current in the wild type-injected oocyte was little changed by the same maneuver.
  • Table 1 shown in Figure 4, compares CF patient genotype with clinical phenotype. Patient genotypes are listed in order of disease severity, and are designated by both alleles separated by a /.
  • the ⁇ F508/F508C compound heterozygotes are clinically unaffected, G551S homozygotes are mildly affected, and the G551 D and ⁇ F508 homozygotes are severely affected.
  • CFTR cRNA To facilitate possible comparisons between expression of Cl conductance and disease severity, we chose, where possible, mutations found in homozygotes so that only a single mutation contributed to the phenotype.
  • 1 ⁇ g of linearized plasmid was incubated with 50 U of T7 RNA polymerase (BRL), 40 U RNAsin (Promega), 2 mM each ATP, UTP, CTP, GTP, in buffer supplied by the enzyme manufacturer at 37°C for 60-90 minutes. RNA was phenol extracted and precipitated, resuspended in H 2 O. RNA quality and quantity was estimated by comparing to standards on an agarose gel.
  • Mutation constructs were generated by oligonucleotide-mediated site- specific mutagenesis of 1.7 kb cDNA fragment containing the first third of the CFTR coding sequence. This fragment was cloned into the pSelect Vector (Promega), and oligonudeotides corresponding to the desired mutation were synthesized and used for second strand priming as described by the supplier. After sequencing to verify the presence of the mutation, the fragment was shuttled into a full length cDNA construct in the vector pBluescript (Stratagene).
  • Figure 2A compares the maximal currents activated by forskolin and IBMX for oocytes injected with cRNA representing five forms of CFTR: wild type, F508C, G551 S, ⁇ F508 and G551D. Maximal responses were defined as current elicited by 5 mM IBMX and 50 ⁇ M forskolin. Attempts to utilize higher concentrations of IBMX were compromised by the lack of solubility of the compound in the Ringers. Values are mean ⁇ standard error. As shown in Figure 2A, if the level of the stimulus is raised sufficiently (10-50 ⁇ M forskolin, 5 mM IBMX) even mutants associated with the most severe clinical symptoms exhibit activity which is 50-60% that of wild type. B. Effects of concentration of IBMX.
  • oocytes expressing wild type CFTR exhibited the greatest sensitivity to activating conditions.
  • Currents in oocytes expressing F508C, a cysteine for phenylalanine substitution at position 508, were only slightly reduced relative to those seen with wild type. This change has been found in combination with ⁇ F508 in an unaffected individual and is considered to be neutral.
  • Next in the rank order was G5518, a serine for glycine substitution at position 551 , which is associated with mild disease. Strong et al., manuscript submitted to N. Engl. J. Med. (1991 ).
  • Representative l-V plots were obtained at maximal activation in oocytes injected with either wild type or ⁇ F508 cRNAs, by ramping the command potential from -100 mV to +80 mV at 100 mV/second. Records were corrected for the small capacitative component of the current.
  • FIGS 3A and 3B Shown in Figures 3A and 3B are records for wild type and ⁇ F508 cRNA-injected oocytes respectively, obtained prior to activation by forskolin and IBMX, after maximal activation and after reducing [Cl] 0 from 106 to 4 mM.
  • the small outward current seen in Figure 3A prior to activation at depolarizing potential was also noted in uninjected oocytes and appears to represent an endogenous Cl conductance activated as the result of voltage-dependant Ca 2+ entry.
  • This current was eliminated in Figure 3B by perfusing the oocyte with a nominally calcium-free Ringers solution. Because this maneuver had no effect on the activation of l M in injected oocytes, all l-V relations (except prestimulation in Figure 3A) were obtained in the Ca -free condition.
  • CFTR suggests that, if CFTR functions as a channel as has been proposed (Anderson et al., Science 253:202 (1991)), then the conduction pathway perse is not compromised by these mutations.
  • One theory which is consistent with the proposed domain structure of CFTR (Riordan et al. Science 245:1066 (1989)) and recent results of site-directed mutagenesis (Anderson et al., Science 253:202 (1991)) is that NBF1 is not a part of the anion selective pore.
  • the behavior of naturally-occurring NBF1 mutant CFTRs also strongly suggests that they are defective in their ability to be activated by the appropriate stimulus.
  • PKA protein kinase A

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Abstract

La fibrose cystique (CF), maladie génétique létale associée à un défaut de transport de Cl, est provoquée par des mutations du gène codant pour le régulateur de conductance transmembrane de fibrose cystique (CFTR). De manière surprenante, non seulement le CFTR de type sauvage, mais églement plusieurs CFTR mutants se produisant naturellement et présentant un défaut dans le premier repli de liaison de nucléotide (NFB1), ont tous exprimé des courants Cl pouvant être activés par cAMP. Le traitement des CFTR mutants avec des concentrations appropriées d'un inhibiteur de méthylxanthine phosphodiestérase (qui accroît les niveaux de cAMP) a produit l'activation de la conductance de Cl à des niveaux proches de ceux de type sauvage. La présente invention ouvre ainsi une nouvelle voie de traitement de la fibrose cystique par l'administration de quantités thérapeutiques de composés qui augmentent les niveaux de cAMP. On peut également déterminer le dosage et la réaction du patient au traitement, ainsi que les efficacités relatives des composés administrés ou destinés à être administrés, en fonction des procédés de l'invention.
PCT/US1992/008346 1991-10-01 1992-09-30 Traitement de la fibrose cystique WO1993007265A1 (fr)

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US769,869 1991-10-01

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010282A1 (fr) * 1993-10-13 1995-04-20 Mcgill University Utilisation d'inhibiteurs de phosphatase pour la preparation d'un medicament destine au traitement de maladies associees aux canaux cellulaires
WO1996006612A1 (fr) * 1994-08-31 1996-03-07 Case Western Reserve University Procede et composition de traitement de la mucoviscidose
EP0897979A3 (fr) * 1997-08-12 2001-09-26 Smithkline Beecham Corporation Clone de cADN SDR2 humaine

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
AMERICAN JOURNAL OF PHYSIOLOGY, Vol. 256, issued 1990, WILLUMSEN et al., "Activation of an Apical C1 Conductace by Ca2+ Inophores in Cystic Fibrosis Airway Epithelia", pages C226-C233. *
AMERICAN JOURNAL OF PHYSIOLOGY, Vol. 259, issued 1990, VENGLARIK et al., "A Simple Assay for Agonist-Regulated CL and K Conductances in Salt-Secreting Epithelial Cells", pages 358-364. *
BERKOW et al., "The Merk Manual of Diagnosis and Therapy, Chapter 34", Published 1982. *
JOURNAL OF CLINICAL INVESTIGATION, Vol. 73, issued June 1984, SATO et al., "Defective Beta Adrenergic Response of Cystic Fibrosis Sweat Glands In Vivo and In Vitro", pages 1763-1771. *
JOURNAL OF CLINICAL INVESTIGATION, Vol. 78, issued 1986, BOUCHER et al., "Na + Transport in Cystic Fibrosis Respiratory Epithelia", pages 1245-1252. *
NEUROSCIENCE, Vol. 10, No. 5, issued 1987, FRIZZELL, "Cystic Fibrosis: a Disease of Ion Channels?", pages 190-193. *
NEW ENGLAND JOURNAL OF MEDICINE, Vol. 325, No. 8, issued 22 August 1991, KNOWLES et al., "Activation by Extracellular Nucleotides of Chloride Secretion in the Airway Epithelia of Patients with Cystic Fibrosis", pages 533-538. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE USA, Vol. 87, issued July 1990, CLIFF et al., "Separate C1 Conductances Activated by cAMP and Ca in C1-Secreting Epithelial Cells", pages 4956-4959. *
TRENDS IN PHARMACOLOGICAL SCIENCE, Vol. 11, issued April 1990, BEAVO et al., "Primary Sequence of Cyclic Nucleotide Phosphodiesterase Isozyme and the Design of Selective Inhibitors", pages 150-155. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010282A1 (fr) * 1993-10-13 1995-04-20 Mcgill University Utilisation d'inhibiteurs de phosphatase pour la preparation d'un medicament destine au traitement de maladies associees aux canaux cellulaires
WO1996006612A1 (fr) * 1994-08-31 1996-03-07 Case Western Reserve University Procede et composition de traitement de la mucoviscidose
US5602110A (en) * 1994-08-31 1997-02-11 Case Western Reserve University Method and composition for treating cystic fibrosis
EP0897979A3 (fr) * 1997-08-12 2001-09-26 Smithkline Beecham Corporation Clone de cADN SDR2 humaine

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