+

WO2007047582A2 - Composes de porphyrine destines a ameliorer la fonction mitochondriale - Google Patents

Composes de porphyrine destines a ameliorer la fonction mitochondriale Download PDF

Info

Publication number
WO2007047582A2
WO2007047582A2 PCT/US2006/040374 US2006040374W WO2007047582A2 WO 2007047582 A2 WO2007047582 A2 WO 2007047582A2 US 2006040374 W US2006040374 W US 2006040374W WO 2007047582 A2 WO2007047582 A2 WO 2007047582A2
Authority
WO
WIPO (PCT)
Prior art keywords
deficiency
porphyrin
mitochondrial
heme
cytochrome
Prior art date
Application number
PCT/US2006/040374
Other languages
English (en)
Other versions
WO2007047582A3 (fr
Inventor
Gino Cortopassi
Eleonora Napoli
Robert Schoenfeld
Alice Wong
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
Publication of WO2007047582A2 publication Critical patent/WO2007047582A2/fr
Publication of WO2007047582A3 publication Critical patent/WO2007047582A3/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Definitions

  • the present invention provides methods and compositions for treating individuals with deficiencies in mitochondrial function, hi some embodiments, the methods comprise administering an effective amount of a porphyrin.
  • the porphyrin is an iron porphyrin. In some embodiments, the porphyrin is heme. In some embodiments, the porphyrin is hemin.
  • the deficiency in mitochondrial function is characterized by a deficiency in iron-sulfur cluster enzyme activity
  • the deficiency in mitochondrial function is characterized by a deficiency in cytochrome activity.
  • the individual is afflicted with an ailment selected fro the group consisting of Friedreich's ataxia (FRDA), Glutaric Aciduria (GA), Parkinson's Disease (PD), Kearns Sayre Syndrome/Chronic Progressive External Ophthalmoplegia (KSS/CPEO), Leber's Hereditary Optic Neuropathy (LHON), Alzheimer's Disease (AD), Cytochrome Oxidase deficiency (COD), Amyotrophic Lateral Sclerosis (ALS), Myoclonic Epilepsy with Lactic Acidosis and Stroke (MELAS), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), and Neurogenic Ataxia with Retinitis Pigmentosum (NARP).
  • FRDA Friedreich's ataxia
  • GA Glutaric Aciduria
  • PD Parkinson's Disease
  • KSS/CPEO Kearns Sayre Syndrome/Chronic Progressive External Ophthalmoplegia
  • LHON Leber's Hereditary Optic
  • the present invention is based on the surprising observation that administration of metalloporphyrins, such as heme, to cells that are deficient in mitochondrial functions result in an increase in those functions.
  • the present invention provides for therapeutic and prophylactic administration of metalloporphyrins to treat diseases, preferably human diseases, associated with, and/or involving, reduced mitochondrial functions.
  • cytochrome heme-containing proteins containing 5 hemes/cytochromes, including: Cytochrome c reductase (cytochromes b and c ⁇ ), cytochrome c, and cytochrome c oxidase (cytochromes a and « 3 ).
  • Cytochrome c reductase cytochromes b and c ⁇
  • cytochrome c cytochrome c oxidase
  • cytochromes a and « 3 Hemes and cytochromes are made by the biosynthetic pathway shown in the Figure 1, and its efficiency is dependent on metabolic status. Without intending to limit the scope of the invention to a particular mechanism, it is believed that porphyrin supplementation may drive cytochrome synthesis, and thus increase the synthesis of mitochondrial proteins that contain those cytochromes, and thereby increase mitochondrial activity.
  • porphyrins can be used according to the methods of the present invention.
  • the porphyrins will be metalloporphyrins.
  • An exemplary metal in metalloporphyrins is iron.
  • Exemplary porphyrins that can be used in the invention include, e.g., heme and hemin (discussed further below).
  • porphyrins that can be used in the invention include, e.g., delta-Aminolevulinic acid hydrochloride, Al(III) Phthalocyanine Chloride Tetrasulfonic Acid, 3,6-Bis(decyl)phthalonitrile, Bilirubin (alpha), Biliverdin dimethyl ester, Bilirubin dimethyl ester, Biliverdin hydrochloride, Bilirubin conjugate, Coproporphyrin I dihydrochloride, Coproporphyrin III dihydrochloride, Coproporphyrin I tetramethyl ester, Coproporphyrin III tetramethyl ester, Cu(II) meso- Tetra(4-carboxyphenyl)porphine, Cu(II) meso-Tetra(4-sulfonatophenyl) porphine (acid form), Chlorin e6, Co(III) Protoporphyrin IX chloride, Cr(III) Mes
  • Heme is an iron-protopo ⁇ hyrin complex consisting of four substituted pyrrole rings linked by -CH group.
  • the complex When the iron atom is in the ferrous state, the complex is called ferroprotopo ⁇ hyrin or heme, and the molecule is electrically neutral.
  • the complex When the iron atom is in the ferric state, the complex is called ferriprotopo ⁇ hyrin or hemin, and the molecule carries a unit positive charge.
  • Heme is an essential molecule to living aerobic organisms and plays a role in various biological reactions. It is an essential component of mitochondrial energy-generating subsystems cytochrome oxidase, cytochrome c, and cytochrome reductase (See Figure 1). Several types of heme, which differ in the composition of the side chains of the pyrrole rings, are present in nature. The final steps of the heme pathway are in the mitochondria, and make heme b which is the most ubiquitous and constitutes the prosthetic moiety of almost all hemeproteins. Heme c, which is made from heme b, is inco ⁇ orated into cytochrome c and cytochrome cl of cytochrome reductase.
  • Heme a also arise from heme b, and is then inco ⁇ orated into cytochrome oxidase, as heme a and a.3. Any such type of heme can be used according to the methods of the invention. Heme biosynthesis makes use of iron-sulfur proteins ferrochelatase and adrenodoxin, which may be consumed by this activity.
  • Hemin is a non-toxic FDA orphan drug which is normally derived from processed red blood cells. It is approved for treatment of porphyria and myelodysplastic syndrome in humans and the pharmacokinetics toxicology of hemin are well understood (Tenheunen, et al. (1987) J Pharm. Pharmocol. 39:780-786; and Volin, et al. (1988) Blood 71:625-628). Chemically, hemin is chloro[7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18- dipropan oato(2-)-N 2 i, N 22 ,N 23 ,N 24 ]iron.
  • Hemin for administration by injection is commercially available from Ovation Pharmaceuticals, Inc. under the trade name Panhematin®. and has been known as hematin.
  • Hematin which is suitable for use according to this invention, is the chemical reaction product of hemin with aqueous sodium carbonate solution.
  • Heme arginate can also be used in the methods of the present invention and is available commercially from Orphan Europe (UK) Ltd. under the tradename Normosang®.
  • Examples of deficiencies in mitochondrial function that can be treated in the methods of the present invention include, but are not limited to, down regulation of expression or activity of electron transport components, ATP synthesis proteins, TCA cycle components, or coproporphyrinogen oxidase (CPOX). These defects also include defects in mitochondrial membrane potential, and defects in ATP synthesis. These defects result in muscle weakness, deafness, diabetes, dementia, ataxia, blindness (optic neuropathy), and cardiomyopathy, and myoclonus.
  • CPOX coproporphyrinogen oxidase
  • Diseases associated with a deficiency in mitochondrial function that can be treated or ameliorated according to methods of the invention include, e.g., FRDA, PD, KSS/CPEO, LHON, PD, AD, COD, MM, MERRF, MELAS, NARP.
  • Deficiencies in mitochondrial function can include deficiencies (compared to levels in healthy individuals) in iron sulfur cluster enzyme activity (including, but not limited to, deficiencies in the activity of one or more of the enzymes aconitase, ferrochelatase, adrenodoxin, NADH Dehydrogenase, Succinate Dehydrogenase, Cytochrome c reductase, electron-transfer flavoprotein) and/or cytochrome c activity.
  • compositions containing metalloporphyrin compounds can be formulated for human and animal prophylactic and therapeutic applications by those having ordinary skill in the art.
  • Pharmaceutical formulations for administering hemin for the treatment of porphyrias are well understood. Consequently, pharmaceuticals for administering metalloporphyrins, including iron porphyrin compounds, to treat diseases associated with deficiency in mitochondrial function can be formulated based on known hemin formulations.
  • individuals suffering from diseases associated with deficiency in mitochondrial function are identified and treated with one or more iron porphyrin compounds.
  • the range of dose amounts and frequency of delivery of iron porphyrin compound to be administered to mammals, and particularly to humans, to be effective in treating, preventing or ameliorating the symptoms of diseases associated with a deficiency in mitochondrial function can be determined by those having ordinary skill in the art.
  • a methodology for determining appropriate dosage includes determining the existing state of disease of a patient; administering at a preselected frequency, a preselected amount of pharmaceutical formulation containing iron porphyrin compound; determining the state of disease exhibited by the patient at a later time when the disorder, if untreated, would have increased; and applying an adjustment to the dosage amount and/or delivery rate to reduce, maintain or increase the effect of preventing or reducing the disease or disease symptoms.
  • Doses of iron porphyrin compound can be delivered, for example, in a single dosage, divided dosages or in a sustained release during a period, e.g., less than 24 hours.
  • Some iron porphyrin compounds, such as hemin, are susceptible to rapid conversion to billirubin and thus are excreted in substantial fraction via the liver. Dosage amount and frequency of administration may need to be increased to compensate for the therapeutic agent that is so purged prior to reaching the target. This need to boost dosage and frequency is primarily an issue for systemic methods of delivery.
  • compositions that include a iron porphyrin compound may be administered by any method that can deliver iron porphyrin to the site in the body of a mammal where activity is to occur. These methods include but are not limited to oral, subcutaneous, transdermal, intravenous, intramuscular, liposomal and parenteral methods of administration.
  • the iron porphyrin compound can be combined with physiologically acceptable carriers, excipients or diluents. Such carriers will be nontoxic to recipients at the dosages and concentrations employed.
  • compositions can entail combining the iron porphyrin compound with buffers, antioxidants such as ascorbic acid, low molecular weight (e.g., less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
  • antioxidants such as ascorbic acid
  • chelating agents such as EDTA, glutathione and other stabilizers and excipients.
  • Neutral buffered saline or saline mixed with serum albumin can be used.
  • a composition of the invention can be formulated as a lyophilized product using appropriate excipient solutions (e.g., sucrose) as diluents.
  • Hemin, hematin and hemin arginate can be, e.g., administered intravenously in sterile liquid dosage forms. Hemin may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. For example, see Remington's Pharmaceutical Sciences, 17th ed., A. R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), p. 842. Panhematin® hemin is sold in single doses as a sterile, lyophilized black powder suitable for intravenous infusion after reconstitution with USP grade sterile water as described in the Physicians Desk Reference. Medical Economics Data Production Co., Montvale, NJ., (1995) pp. 447-448.
  • heme c cytochrome c
  • cytochrome c mitochondrial preparations obtained from 3 controls and 5 FRDA mutant lymphoblast lines, untreated or treated with 5 ⁇ M hemin for 18 hours. See Figure 2. Both the levels of heme c and cytochrome c in Friedreich's ataxia mutants are significantly lower than the controls (p ⁇ 0.05); the analysis in the same cell lines after treatment with hemin shows a significant and complete rescue of the heme c deficiency (p ⁇ 0.01).
  • Hemin stimulates the expression of several mitochondrial proteins.
  • Hemin stimulates gene expression in multiple cell types.
  • the frataxin gene encodes a mitochondrial protein whose deficiency causes Friedreich's ataxia, heme deficiency, and iron-sulfur cluster deficiency.
  • the frataxin gene was knocked down by siRNA technology in human cells, and heme deficiency and iron- sulfur cluster deficiency was observed.
  • Hemin supplementation restored the activity of the iron-sulfur cluster enzyme adrenodoxin to normal levels, and the mean activity of cytochrome oxidase increased. Thus hemin not only stimulates mitochondrial proteins but also restores iron-sulfur functions.
  • Lymphocytes were grown in RPMI 1640 supplemented with 500 mg/L glutamate, 1 mM sodium pyruvate, 50 ⁇ g/ml uridine, 100 ⁇ M nonessential amino acids (Invitrogen, Carlsbad, CA), 20% fetal calf serum and penicillin/streptomycin.
  • Human 143B osteosarcoma cells were grown in Dulbecco's modified Eagle's medium containing 4.5 g/L glucose, 110 mg/L pyruvate, supplemented with 10% (v/v) fetal bovine serum, 100 units/mL penicillin, and 0.1 mg/mL streptomycin.
  • Mitochondria were isolated from 3 controls and 5 FRDA mutant lines of human immortalized lymphoblasts following the method of Trounce et al (Trounce,et al. Methods Enzymol 264: 484-509 (1996)). Approximately IxIO 8 cells were harvested by centrifugation and the pellet was re-suspended with 4 ml of isolation buffer (210 mM mannitol, 70 mM sucrose, ImM EGTA and 5mM HEPES, pH 7.2) for each gram of packed cells, treated with a final concentration of 0.3 mg/ml digitonin for 1 min 30 sec and centrifuged at 3500 rpm for 5 minutes.
  • isolation buffer 210 mM mannitol, 70 mM sucrose, ImM EGTA and 5mM HEPES, pH 7.2
  • the pellet was then resuspended with 5 ml for each gram of initial packed cells and homogenized with a chilled class homogenator (20 passes). After several centrifugation steps at 1510 rpm, the final supernatant was centrifuged at lOOOOg and the final pellet was suspended with 0.1 ml of isolation buffer per gram of starting cells, giving a protein concentration of approximately 8-12 mg/ml. For determination of mitochondrial protein concentration, 5 ⁇ l of the mitochondrial suspension was diluted 1:20 in double distilled water and the protein concentration was estimated using the Bradford assay (Bio-Rad).
  • the lysates were prepared resuspending the mitochondrial pellet in about 100 ⁇ l per initial gram of packed cell of the following lysis buffer: 5OmM Tris, pH 7.8, 100 mM NaCl, 1 mM PMSF and 1% detergent (IGEP AL-C A630) for 30 minutes at 0°C and insoluble material removed by centrifugation at 1600Og. The supernatant was collected, the protein amount evaluated using the Bradford assay (Bio-Rad) and the mitochondrial fraction stored at -80°C.
  • Equal amounts of lysates (40 ⁇ g) untreated or treated with hemin were resolved on a 15% SDS-polyacrylamide gel and then transferred to a nitrocellulose membrane (Millipore, Bedford, MA) by electroblotting. After blocking with 4% non-fat dry milk, the blot was incubated with anti-cytoclirome c (1:1500), or anti-COXII (1:2000), or anti-Complex I- 39Kda subunit (1:1000) and was developed with AP-conjugated secondary antibodies using a chemiluminescent substrate.
  • the heme staining is based on the oxidation of ⁇ -dianisidine, a probe which, in presence of hydrogen peroxide (H 2 O 2 ), can be oxidized by the peroxidase activity of some heme-proteins (such as cytochrome c) changing color.
  • the gel was soaked in a solution of 5OmM trisodium citrate, 0.7% H 2 O 2 and 1 mg/ml o-dianisidine for 40-60' at 45°C.
  • 0.5 ⁇ g of horse heart purified cytochrome c was used as positive controls.
  • the band in correspondence of cytochrome c became evident after 20 minutes.
  • Statistical analysis of the data was analyzed by the data.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de porphyrine utilisés pour l'amélioration de maladies impliquant des déficiences de la fonction mitochondriale.
PCT/US2006/040374 2005-10-18 2006-10-16 Composes de porphyrine destines a ameliorer la fonction mitochondriale WO2007047582A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72807305P 2005-10-18 2005-10-18
US60/728,073 2005-10-18

Publications (2)

Publication Number Publication Date
WO2007047582A2 true WO2007047582A2 (fr) 2007-04-26
WO2007047582A3 WO2007047582A3 (fr) 2007-10-25

Family

ID=37963170

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/040374 WO2007047582A2 (fr) 2005-10-18 2006-10-16 Composes de porphyrine destines a ameliorer la fonction mitochondriale

Country Status (1)

Country Link
WO (1) WO2007047582A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007103427A3 (fr) * 2006-03-06 2007-11-08 Xiang H Wang Usage médical de bilirubine et d'analogues structuraux de celle-ci
EP2473171A4 (fr) * 2009-09-02 2012-07-11 Univ Colorado Regents Procédés de traitement de troubles mitochondriaux à l'aide de métalloporphyrines
US9452989B2 (en) 2012-05-24 2016-09-27 University Of Utah Research Foundation Compounds, sensors, methods, and systems for detecting gamma radiation
CN113813371A (zh) * 2021-10-09 2021-12-21 苏州大学 血红素及其类似物在制备线粒体疾病治疗药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ATAMNA ET AL.: 'Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging' PNAS vol. 99, no. 23, November 2002, pages 14807 - 14812 *
DO ET AL.: 'Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation' TRANSPLANTATION vol. 73, no. 3, February 2002, pages 469 - 472 *
SCHILLER ET AL.: 'Intravenous Hemin as Prophylaxis of Allograft Function Following Second Liver Transplant for Erythropoietic Protoporphyria' BLOOD (ASH ANNUAL MEETING ABSTRACTS) vol. 104, 2004, page ABSTR. NO. 3677 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007103427A3 (fr) * 2006-03-06 2007-11-08 Xiang H Wang Usage médical de bilirubine et d'analogues structuraux de celle-ci
EP2473171A4 (fr) * 2009-09-02 2012-07-11 Univ Colorado Regents Procédés de traitement de troubles mitochondriaux à l'aide de métalloporphyrines
US9452989B2 (en) 2012-05-24 2016-09-27 University Of Utah Research Foundation Compounds, sensors, methods, and systems for detecting gamma radiation
CN113813371A (zh) * 2021-10-09 2021-12-21 苏州大学 血红素及其类似物在制备线粒体疾病治疗药物中的应用

Also Published As

Publication number Publication date
WO2007047582A3 (fr) 2007-10-25

Similar Documents

Publication Publication Date Title
AU2021225263B2 (en) Treatment of retinitis pigmentosa with n-acetylcysteine amide
Jin et al. Mitochondria-targeted antioxidants for treatment of Parkinson's disease: preclinical and clinical outcomes
US6583132B1 (en) Oxidant scavengers
JP7631200B2 (ja) 放射線皮膚炎の予防及び治療、並びに皮膚ライトニング、皮膚ホワイトニング、並びに皮膚改善のためのｎ－アセチルシステインアミド（ｎａｃａ）及び（２ｒ，２ｒ’）－３，３’－ジスルファンジイルビス（２－アセトアミドプロパンアミド）（ｄｉｎａｃａ）
AU7386500A (en) Compositions and methods for the treatment of parkinson's disease
WO2007047582A2 (fr) Composes de porphyrine destines a ameliorer la fonction mitochondriale
KR100951606B1 (ko) 안과 질환 및 질병의 치료를 위한 과산화물 디스뮤타제모방체
US20020198231A1 (en) Compositions and methods for the treatment of Parkinson's disease
CN115151251A (zh) 用于治疗氧化应激的疾病和损伤的前药
EA014076B1 (ru) Применение рибозы-цистеина для лечения гипоксии
US9138423B2 (en) Use of inhibitors of porphobilinogen deaminase in the treatment of congenital erythropoietic porphyria
JP6199579B2 (ja) ミトコンドリア機能回復促進剤
US20250009692A1 (en) Micronutrient composition to prevent and reverse protein glycation during oxidative stress in human
JPH0411525B2 (fr)
US10016489B2 (en) Methods and compositions for treating diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06836333

Country of ref document: EP

Kind code of ref document: A2

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载