WO2007085036A1 - Traitement de l'ataxie de friedreich - Google Patents

Traitement de l'ataxie de friedreich Download PDF

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Publication number
WO2007085036A1
WO2007085036A1 PCT/AT2007/000035 AT2007000035W WO2007085036A1 WO 2007085036 A1 WO2007085036 A1 WO 2007085036A1 AT 2007000035 W AT2007000035 W AT 2007000035W WO 2007085036 A1 WO2007085036 A1 WO 2007085036A1
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Prior art keywords
frataxin
decreased expression
expression
ataxia
treatment
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PCT/AT2007/000035
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English (en)
Inventor
Barbara Scheiber-Mojdehkar
Brigitte Sturm
Bernhard Gmeiner
Stylianos Kapiotis
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Medizinische Universität Wien
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Publication of WO2007085036A1 publication Critical patent/WO2007085036A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention is concerned with a pharmaceutical preparation for the treatment of Friedreich' s ataxia and for the treatment or prevention of diseases associated therewith.
  • FRDA Friedreich's ataxia
  • Friedreich' s ataxia is caused by a GAA-trinucleotide expansion in the frataxin gene located on chromosome locus 9ql3, resulting in a reduced expression of frataxin, a small mitochondrial protein. Due to the mitochondrial localization of frataxin, the neurological and cardiological degenerations observed in FRDA are thought to be the result of a mitochondrial defect.
  • the exact physiological function of frataxin- is unknown, but it may be involved in mitochondrial iron homeostasis and/or assembly of iron- sulfur (FeS) proteins and heme synthesis. Intramitochondrial iron accumulation has been postulated to initiate the production of hydroxyl radicals by Fenton chemistry, leading to inactivation of FeS enzymes, lipid peroxidation and damage to nucleic acids, proteins and finally resulting in cell death.
  • the present invention provides the use of porphyrin compounds comprising Ca 2+ , Zn 2+ or Mg 2+ for the production of a pharmaceutical preparation for the treatment of Friedreich' s ataxia or for the treatment or prevention of a disease associated therewith.
  • porphyrin compounds comprising Ca 2+ , Zn 2+ or Mg 2+ have the potential to increase the expression of frataxin. Due to their nature, these porphyric compounds especially, the Mg 2+ porphyrins can be administered to humans over long periods of time, if necessary over the whole life-time.
  • the treatment according to the present invention is suitable to treat or prevent not only FRDA itself but also all diseases which are connected or caused by FRDA (diseases associated with FRDA) .
  • Mg, Zn and Ca ions have the specific advantage that a change in charge does not occur in the course of administration (e.g.
  • porphyrin compounds to be used according to the present invention must be non-toxic (in the amount and/or dose and/or time required to be administered) and provided to the patient in an efficient dosage.
  • This dosage may be determined for each porphyrin compound in an individual manner with standard methods and the methods described herein.
  • the exact and optimal amount of porphyrin compounds to be administered also depends on the individual potency of increasing expression of frataxin (e.g. easily to be determined by the cellular model system provided in the example section of the present application or simply by comparison with related porphyrins) , on the biological availability of the porphyrins in the patients (depending on e.g.
  • solubility mode of application, pharmaceutical formulation (including deriv- atisation by addition of targeting or solubilising molecules, such as PEGylation, etc.).
  • toxicity is defined according to the appropriate international guidelines explained and referred to in R ⁇ mpp's Chemielexikon, 10 th ed. (1999), page 4596. In case of internationally differing limiting or- maximum values or dosages, the respective values or dosages valid in Austria (or EU) should apply.
  • the porphyrin preparations to be used according to the present invention should preferably have a biological activity at least comparable to the activity of Cu-chlorophyllin on frataxin-ex- pression in primary lymphocytes from patients with Friedreich's ataxia as described in the example section of the present application.
  • Cu-porphyrins may be given for treatment of FRDA over a shorter period of time, long term treatment of FRDA (i.e. treatments over 3 months, especially more than 1 year) should only be performed with Mg-, Zn- or Ca-porphyrins.
  • porphyrin preparations and compositions according to the present invention are preferred, which have a biological activity on frataxin-expression of at least 20%, preferably at least 50%, of the activity of Cu-chlorophyllin in this primary lymphocyte test system, i.e. that the same effect with respect to frataxin-expression is reached with maximal the 5-fold dose, preferably with maximal the double dose (of course without being toxic in these doses with the toxicity being defined as outlined above) .
  • the porphyrin compounds are therefore always administered in a suitable manner to enable the biological activity for increasing the expression of frataxin.
  • frataxin levels should be established which reduce the risk for the patient to be affected by the diseases associated with FRDA.
  • frataxin levels should be established over a suffificent term, e.g. over a whole day (so that daily dosage is sufficient) , even more preferred over a duration of at least three days, of at least five days, of at least 7 days or especially over at least two weeks or at least four weeks.
  • Suitable test systems for defining the possible range for such dosages for any porphyrin compound, including mixtures of such compounds, are readily available and workable by the skilled man in the art; preferred systems are also described in the example section of the present application.
  • any Ca-, Zn- or Mg-porphyrin (IOPAC nomenclature of tetrapyrroles : TP-O, TP-I, TP-2, TP-3, TP- 4, TP-5, TP-8 and TP-9) compound can be used which shows efficient up-regulation of frataxin expression in a patient being affected by FRDA when using non-toxic dosages.
  • IOPAC nomenclature of tetrapyrroles TP-O, TP-I, TP-2, TP-3, TP- 4, TP-5, TP-8 and TP-9
  • TP-O, TP-O, TP-I, TP-2, TP-3, TP- 4, TP-5, TP-8 and TP-9 compound can be used which shows efficient up-regulation of frataxin expression in a patient being affected by FRDA when using non-toxic dosages.
  • mixtures of porphyrin compounds have to be regarded as uses of a porphyrin compound according to
  • Preferred porphyrin compounds to be used according to the present invention include those porphyrins which are already accepted as being well tolerated by and suitably administratable to humans.
  • Examples of such porphyrine compounds are chlorophylls (chlorophyll a, chlorophyll b, chlorophyll C x , chlorophyll C 2 , chlorophyll d, bacteriochlorophyll a, bacteriochlorophyll b, meso- chlorophyll a or mixtures of one or more of such chlorophylls) , chlorophyllins with the central ion being exchanged to Mg, Zn or Ca (Mg-, Zn- or Ca-chlorophyllins) ; esters thereof with 1 to 20 C-atoms preferably at the carbonyl residue attached to C 13 or C 17 or both), corrins (such as vitamin B12), corroles, phthalocy- anines and metal complexes thereof.
  • Preferred porphyrin compounds according to the present invention are porphyrins extracted from natural sources, especially natural plant sources or chemically synthesised versions of such porphyrins present in natural sources-
  • synthetic porphyrins not existing as such in nature or porphyrin compounds altered by biochemical or organic chemistry may be used according to the present invention if they can be administered to FRDA patients in efficient amounts to increase frataxin levels.
  • a preferred embodiment of the present invention is to use Ca-, Zn- or Mg-chlorophyllin compositions as porphyrin compound.
  • Zn-, Ca- or Mg-porphyrin compounds to be used according to the present invention are known and described in the art, e.g. in QS 4,851,339, US 5,066,274, US 5,308,861, US 5,399,583, US 6,632,808, and especially the PEGylated porphyrins described e.g. in US 6,147,207 A and US 2004/0186285 A as well as their non-PEGylated counterparts and metal complexes of the PEGylated and non-PEGylated porphyrins .
  • the compounds according to the present invention may additionally comprise lipophilic cation moieties (e.g. as described in US 2004/0029851 Al), preferably ammonium or phosphonium moieties, especially triphenyl phosphonium.
  • porphyrin preparation comprising Zn 2+ -, Ca2 + - or Mg 2+ -porphyrins to be used for the treatment of FRDA according to the present invention may contain also mixtures of different porphyrins. Also other ingredients, such as further active ingredients, pharmaceutically acceptable carriers, etc. can be included in such porphyrin preparations
  • the pharmaceutical preparation according to the present invention comprising Ca 2+ -, Zn 2+ - or Mg 2+ -porphyrins can be administered in any pharmaceutically acceptable form to increase frataxin expression in FRDA patients.
  • Suitable forms are unit dosage forms, such as tablets, effervescent tablets, powder dragees, capsules, sachets, etc., as solution for injection (e.g. intraveneous or intramuscular) or infusion, as an orally applicable solution, suppositories, nasal spray, nanoparticles or implant; or as lyo- philized product, e.g. by the intravenous, intramuscular, intracranial or intranasal route (as nose spray) .
  • the invention is further directed to a new medical application of a pharmaceutical preparation containing porphyrin compounds comprising a complexed Ca 2+ , Zn 2+ or Mg 2+ ion to increase the expression of the protein frataxin.
  • the porphyrin compound according to the present invention may be administered at a dose between 1 nanogram and 0.5 to 1 gram per kg body weight (for example 1 microgram to 100 micrograms per kg) , without appreciable toxicity, such as cytotoxicity.
  • the porphyrin compounds may be administered by a wide variety of routes (direct administration into the CNS, intracranial ventricular, intrathecal, aural, transdermal, intravenous, intramuscular, subcutaneous, oral, olfactory, ocular and rectal)
  • the porphyrin compounds of the present invention are particularly advantageous because many of them are believed to readily pass the blood brain barrier. Compounds having increased lipophilicity, or in pharmaceutical carriers such as liposomes, will have enhanced penetration of the CNS.
  • a porphyrin compound is used for which sufficient frataxin increase is reached with a maximal dose of 1 g/day, preferably of 500 mg/day, especially a maximum dose of 300 mg/day (well tolerated with no side effects) .
  • Preferred doses are - referred to chlorophyllin - 1 to 1000 mg per day, preferably 5 to 500 mg per day, especially 10 to 300 mg per day.
  • administration of the porphyrin compound should be established to enable a concentration of the porphyrin compound in the blood of the patient of above 200 nanoM, preferably above 1 microM, especially above 5 microM.
  • the present invention is based on the finding that porphyrin compounds can significantly increase the expression of frataxin in various cell types, e.g. in primary lymphocytes from FRDA patients in a dose-dependent manner. Therefore porphyrin compounds described above can be used for the production of a pharmaceutical preparation for the treatment of Friedreich' s ataxia or for the treatment or prevention of a disease associated therewith.
  • porphyrin compounds comprising a complexed Ca 2+ , Zn 2+ or Mg 2+ for the production of a pharmaceutical preparation for the treatment or prevention of a disease associated with Friedreich' s ataxia, in particular
  • the present invention relates to the treatment of a disease which is characterized by a decreased expression of frataxin:
  • diseases may be treated by administration of an effective amount of porphyrin to a patient as described herein.
  • All preferred embodiments e.g. with respect to Zn 2+ -, Ca 2+ - and Mg 2+ -porphyrins, (pharmaceutical) preparations of porphyrin, etc., as described above for FRDA also apply to this aspect of the present invention.
  • the diseases associated with a decreased frataxin expression are selected from the group consisting of heart diseases, especially cardiomyopathies, diabetes, especially diabetes mellitus, neurodegenerative diseases, especially any form of ataxia, bone deformations, especially scoliosis and pes cavus, nystagmus, impaired hearing, eye diseases, especially optic atrophy, and cancer.
  • heart diseases especially cardiomyopathies, diabetes, especially diabetes mellitus, neurodegenerative diseases, especially any form of ataxia, bone deformations, especially scoliosis and pes cavus, nystagmus, impaired hearing, eye diseases, especially optic atrophy, and cancer.
  • Fig.l shows increase of frataxin expression in human primary lymphocytes of FRDA patients upon exposure to Cu-chlorophyllin;
  • Figs.2 and 3 show increase of frataxin expression mouse embryo carcinoma cells (P 19) , differentiated to neurons using retinol upon exposure to Cu-chlorophyllin (Fig.2) and Mg-chlorophyllin (Fig.3) .
  • Figs .4 and 5 show increase of frataxin protein levels in mice (heart (Fig.4) and brain (Fig.5)).
  • Lymphocytes - Lymphocytes from 7 FRDA patients were collected from fresh blood samples and isolated with Biocoll Separating Solution, density 1.077g/ml (Biochrom AG, Berlin, Germany) according to the manufacturer's procedure. Finally, cells were diluted to a density of IxIO 6 cells and cultured in RPMI media supplemented with 10% fetal calf serum, 2 mM L-glutamine and antibiotics and were used for experiments .
  • Neuronal cells The P19 clone was obtained from the European Cell Culture Collection (ECACC Cat. Nr. 95102707, Salisbury, UK) . Cells were cultured in ⁇ -modified Eagle' s medium ( ⁇ -MEM) supplemented with 7.5% calf serum (Euroclone, Vienna, Austria) and 2.5% fetal bovine serum (Gibco, Vienna, Austria) , 2 mM L-glutamine, lOml/1 essential amino acids and antibiotics in a 5% CO 2 humidified chamber. Cellular differentiation was carried out as described by Santos et al. (Santos et al., Hum.MoI. Genet .10 (2001), 1935-1944) .
  • frataxin was detected by Western blot. After treatment with porphyrins for the indicated periods and after extensive washings the cells were lysed with cell culture lysis reagent (Promega, Vienna, Austria) and transferred to a microcentrifuge tube. Fifty micrograms of proteins were separated on 12% SDS (sodium dodecyl sulfate) - polyacrylamide gel electrophoresis under non-reducing conditions using Prosieve 50 Gel solution (BMA, BioWhittaker from Biozym, Vienna, Austria) and Tris/Tricine-elec- trode buffer (0.1 M Tris, 0.1 M Tricine, 0.1% SDS, pH 8.3) and electroblotted onto nitrocellulose membranes. Primary antibody was directed against mature frataxin (Cavadini et al., 2002) and - li as a secondary antibody a goat-anti rabbit HRP antibody (1:10000) (DAKO) was used.
  • SDS sodium dodecyl sulfate
  • Frataxin expression in neuronal cells increases after treatment with Cu-chlorophyllin.
  • Frataxin expression in neuronal cells increases after treatment with Mg-chlorophyllin.
  • Density of the frataxin band of the control was set as Ia. u. (arbitrary units) . Values represent means ⁇ SEM of 3 different experiments. Differences were examined for statistical significance using the paired t-test. Significant differences vs. control are marked in the figures with * (p ⁇ 0.05), ** (p ⁇ 0.01) and *** (p ⁇ 0.001) .
  • sacrification of the mice heart and brain tissues were homogenized and treated with solubilisation buffer. Proteins were separated by 12% SDS- PAGE.

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Abstract

L'invention concerne l'utilisation de composés de porphyrine comprenant un ion Ca2+, Zn2+ ou Mg2+ complexé pour produire une préparation pharmaceutique destinée au traitement de l'ataxie de Friedreich ou au traitement ou à la prévention d'une maladie associée à celle-ci.
PCT/AT2007/000035 2006-01-26 2007-01-26 Traitement de l'ataxie de friedreich WO2007085036A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011009890A2 (fr) 2009-07-23 2011-01-27 Novartis Ag Utilisation de dérivés de azabicycloalkyle ou de dérivés de pyrrolidine-2-one
US10537539B2 (en) 2009-09-22 2020-01-21 Novartis Ag Use of nicotinic acetylcholine receptor alpha 7 activators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632808B1 (en) * 1998-08-11 2003-10-14 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors of amyloid formation
EP1378753A1 (fr) * 2002-07-01 2004-01-07 Myocontract Ag Procédé de criblage et composés destinés au traitement de la maladie de friedreich
WO2006050819A1 (fr) * 2004-11-09 2006-05-18 Medizinische Universität Wien Preparation pharmaceutique pour le traitement de l'ataxie de friedreich

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632808B1 (en) * 1998-08-11 2003-10-14 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors of amyloid formation
EP1378753A1 (fr) * 2002-07-01 2004-01-07 Myocontract Ag Procédé de criblage et composés destinés au traitement de la maladie de friedreich
WO2006050819A1 (fr) * 2004-11-09 2006-05-18 Medizinische Universität Wien Preparation pharmaceutique pour le traitement de l'ataxie de friedreich

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ISAYA G ET AL: "Functional studies of frataxin", ACTA PAEDIATRICA, vol. 93, no. Suppl. 445, May 2004 (2004-05-01), pages 68 - 71, XP009082916, ISSN: 0803-5253 *
KAPIOTIS STYLIANOS ET AL: "Copper- and magnesium protoporphyrin complexes inhibit oxidative modification of LDL induced by hemin, transition metal ions and tyrosyl radicals", FREE RADICAL RESEARCH, vol. 39, no. 11, November 2005 (2005-11-01), pages 1193 - 1202, XP009082927, ISSN: 1071-5762 *
SARSERO JOSEPH P ET AL: "Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia.", THE JOURNAL OF GENE MEDICINE JAN 2003, vol. 5, no. 1, January 2003 (2003-01-01), pages 72 - 81, XP009082996, ISSN: 1099-498X *
STURM B ET AL: "Recombinant human erythropoietin: effects on frataxin expression in vitro", EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, vol. 35, no. 11, November 2005 (2005-11-01), pages 711 - 717, XP002431406, ISSN: 0014-2972 *
VONCKEN MAX ET AL: "Friedreich ataxia: Update on pathogenesis and possible therapies.", NEUROGENETICS (HEIDELBERG), vol. 5, no. 1, February 2004 (2004-02-01), pages 1 - 8, XP002431407, ISSN: 1364-6745 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011009890A2 (fr) 2009-07-23 2011-01-27 Novartis Ag Utilisation de dérivés de azabicycloalkyle ou de dérivés de pyrrolidine-2-one
US10537539B2 (en) 2009-09-22 2020-01-21 Novartis Ag Use of nicotinic acetylcholine receptor alpha 7 activators
US11096916B2 (en) 2009-09-22 2021-08-24 Novartis Ag Use of nicotinic acetylcholine receptor alpha 7 activators

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