WO2004006935A1 - Utilisation de composes activant le trajet de la proteine srebp - Google Patents

Utilisation de composes activant le trajet de la proteine srebp Download PDF

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WO2004006935A1
WO2004006935A1 PCT/EP2003/007504 EP0307504W WO2004006935A1 WO 2004006935 A1 WO2004006935 A1 WO 2004006935A1 EP 0307504 W EP0307504 W EP 0307504W WO 2004006935 A1 WO2004006935 A1 WO 2004006935A1
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abcd2
srebp
ald
disease
activate
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PCT/EP2003/007504
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Johannes Berger
Isabelle Weinhofer
Sonja Forss-Petter
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Austria Wirtschaftsservice Gesellschaft mit beschränkter Haftung
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Publication of WO2004006935A1 publication Critical patent/WO2004006935A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

  • X-linked adrenoleukodystrophy is a severe neurodegener- ative disorder with impaired very long-chain fatty acid (VLCFA) metabolism (1) .
  • X-ALD (McKusic 300100) encompasses widely differing clinical phenotypes reflecting two distinct pathological mechanisms: an inflammatory demyelinating process leading to rapidly progressing, fatal cerebral X-ALD, and a slowly progressing distal axonopathy leading primarily to adrenomyel- oneuropathy (AMN) in young adults. Cerebral X-ALD is most commonly of childhood-onset, but a larger proportion of adult AMN patients develop the inflammatory form than had been realised in the past.
  • X-ALD treatments for X-ALD have been suggested in WO 89/08095 A (treatment with Lorenzo's Oil), WO 01/93802 A (use of riluzole or one of its pharmaceutically acceptable salts for the prevention and treatment of X-ALD) and US 5644045 A (gene therapy in X-ALD using the ABCDl-gene) .
  • the cholesterol-lowering drug lovastatin, a 3-hydroxy-3-methylglutaryl coen- zy e A reductase inhibitor was proposed as a new therapeutic agent for X-ALD (2) .
  • ABCDl-gene alternatively termed ALD
  • ALD peroxisomal membrane protein that belongs to the superfamily of ABC-transporters .
  • overexpression of ABCD2 the protein most closely related to ABCDl, is able to functionally replace ABCDl protein concerning the accumulation of VLCFA in cultured fibroblasts of X-ALD patients lacking ABCDl protein (7) .
  • ABCD2 does not compensate for ABCDl-deficiency in X-ALD patients or in X-ALD mice.
  • ABCD2 The reason for this appears to be the complementary expression patterns of ABCDl and ABCD2, and a low level ABCD2 expression does not compensate for loss of ABCDl protein in disease-relevant cell types.
  • induction of ABCD2 expression represents a novel therapeutic strategy for X-ALD.
  • the present invention provides the use of compounds that activate the sterol regulatory element binding protein (SREBP) pathway for the preparation of a drug for inducing the adrenoleukodystrophy-related protein (ALDRP; ABCD2) in patients suffering from neurodegenerative or neuroinflammatory disorders.
  • SREBP sterol regulatory element binding protein
  • ADRP adrenoleukodystrophy-related protein
  • This invention is concerned with the description of a functionally tightly linked group of compounds able to activate SREBP maturation and thus have the potential to induce ABCD2 gene expression. Consequently, these compounds can be used for the preparation of a medicament indicated to treat and prevent X-ALD and other neurodegenerative or neuroinflammatory disorders associated with cholesterol metabolism and oxidative stress, e.g. Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis.
  • peroxisome proliferator fenofibrate has been shown to induce ABCD2 in a mechanism dependent on a class of transcription factors known as peroxisome proliferator activated receptor alpha (PPARalpha) in the liver but not in the brain of rodents (9) .
  • PPARalpha peroxisome proliferator activated receptor alpha
  • the brain is the organ most severely affected in X-ALD patients, it is essential for a therapeutical agent to enter this organ.
  • treatment of X-ALD patients with the fenofibrate analoga clofibrate did not result in normalisation of the pathognomonic levels of VLCFA in tissues of these patients (10) .
  • a SREBP-dependent mechanism is not expected as these substances do not induce luciferase activity of a reporter construct containing the SRE sequence of the ABCD2 promoter (pGL-E21uc, details are described below) , an assay system that is used for the identification of compounds able to stimulate ABCD2 gene expression involving SREBPs .
  • One novel key invention leading to the present invention is the fact that ABCD2 gene expression is induced in cultured human fibroblasts and monocytes upon sterol depletion via a mechanism requiring the activation and direct binding of a class of sterol sensing transcription factors known as sterol regulatory element binding proteins (SREBPs) to the promoter region of the ABCD2 gene. Cholesterol regulates transcription of several genes. Each of these sterol-sensitive genes contains at least one sterol regulatory element (SRE) or palindromic sequences called E-boxes within their promoter regions, through which SREBPs activate transcription (11,12). SREBP are transcription factors that belong to the basic helix-loop-helix leucine zipper family.
  • SREBP sterol regulatory element binding proteins
  • SREBPs are synthesised as precursor proteins that remain bound to the endoplasmatic re- ticulu and the nuclear envelope in the presence of sufficient sterol concentrations. Upon sterol deprivation, the precursor protein undergoes a sequential two-step cleavage process to re- lease the NH 2 -terminal portion (13) . This mature SREBP then enters the nucleus and activates the transcription of genes involved in cholesterol and fatty acid synthesis (14,15).
  • SREBPla and SREBPlc are derived from a single gene through the use of alternate promoters and SREBP2 from a different gene.
  • SREBPla is the more common isoform and is a stronger activator of transcription with a wider range of target genes than SREBPlc because of a longer transactivation domain (16) .
  • Transgenic mouse studies have shown that SREBPlc plays a more active role in regulating the transcription of genes involved in fatty acid synthesis than those involved in cholesterol synthesis, whereas SREBPla activates both (16,17).
  • SREBP2 is known to be actively involved in the transcription of cholesterogenic enzymes (18) (reviewed in 19) . This invention clearly provides a novel and unexpected pathway by which ABCD2 gene expression can be induced pharmacologically and thus closely links ABCD2 function to cholesterol metabolism.
  • ABCD2 expression is induced when cells are treated with H 2 0 2 or ethanol, a condition resulting in oxidative stress.
  • the ABCD2 protein seems to play a role in cells facing oxidative stress, which is associated with diseases such as cancer and atherosclerosis but also major neurodegenerative and neuroin- flammatory disorders, e.g. Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis.
  • the upregulation of ABCD2 gene expression might provide a novel therapeutic strategy for other diseases than X-ALD.
  • Neuroinflammatory processes induced in part by pro-inflammatory cytokines, yield enhanced reactive nitric oxide species as well as other unknown components that have neurotoxic properties and are formed by the activity of inducible nitric oxide synthase.
  • a method for the inhibition of inducible nitric oxide synthase and the production of nitric oxide is described as well as methods for treating various disease states, such as X-ALD, multiple sclerosis, Alzheimer's disease and septic shock using inhibitors of iNOS and cytokine induction.
  • the proposed mechanism is independent from the present invention, as ABCD2 gene expression is neither linked to inducible nitric oxide synthase activity nor to the production of nitric oxide.
  • compounds that activate the SREBP pathway are used for the preparation of a medicament for the treatment and prevention of neurodegenerative or neuroin- flammatory disorders.
  • the medicament is administered to the patient in an amount effective for activating the SREBP pathway and improving the disorder or in an amount effective for prevention of such disorders .
  • the neurodegenerative or neuroinflammatory disorder is preferably selected from the group consisting of X-linked ad- renoleukodystrophy (X-ALD) (especially fatal cerebral X-ALD and adrenomyeloneuropathy (AMN) , multiple sclerosis (MS) , Alzheimer's disease, amyothrophic lateral sclerosis (ALS) , Parkinson's disease (PD) and Huntington's disease (HD) .
  • X-ALD X-linked ad- renoleukodystrophy
  • AMD adrenomyeloneuropathy
  • MS multiple sclerosis
  • Alzheimer's disease amyothrophic lateral sclerosis
  • PD Parkinson's disease
  • HD Huntington's disease
  • any compounds that are able to activate the SREBP pathway and that are tolerated by patients to an acceptable level might be used to induce ABCD2 gene expression in order to provide a novel therapeutic strategy for X- ALD but also for other neurodegenerative, neuroinflammatory diseases linked to oxidative stress.
  • This group of substances strictly includes only those compounds that are able to induce ABCD2 gene expression by activating SREBP maturation and binding to the ABCD2 promoter under standard cell culture cholesterol conditions (standard cell culture media supplemented with 10% fetal calf serum, 2 mM L-glutamine, 50u/ml penicillin and 100 ⁇ g/ml streptomycine) .
  • This group of compounds consists for example of SREBP pathway activating cholesterol lowering drugs, especially (3 , 4 ⁇ , 5 ) -4- (2-propenyl-cholestan-3-ol) and 7,20:20, 21-bis [ (methylenebis (oxy) ] -6-dimethylaminomethyl-3-eth- oxy-pregn-3-ene-ll-beta-ol, non steroidal molecules that activate the SREBP pathway, especially 4- [ (4-chlorobenzoyl) amino] -N- [4- [4- [2, 4-bis (ethoxy) -phenyl] -1-piperidinyl]butyl] -benzamide, 4- [ (4-chlorobenzoyl) amino] -N- [4- [4- [2-ethoxy-4-ethylphenyl] -1- piperidinyl] butyl] -benzamide, 4-benzoyl-N- [4- [4- [2-methoxy-4- (1-
  • This group of compounds strictly excludes substances that have been suggested for X-ALD therapy, e.g. lovastatin, sodium phenylacetate, forskolin, 8-bromo cAMP, rolipra , 4-PBA, fenofibrate and clofibrate. This is based on the finding that these compounds were found to have no effect in the luciferase-based assay system for identification of compounds able to stimulate ABCD2 expression in a SREBP-dependent manner as described in the example section.
  • Fig. 1 shows ABCD2 mRNA levels in monocytes/microglia and fibroblasts
  • Fig. 2 shows VLCFA levels in fibroblasts
  • Fig. 3a, b and c show the characterisation of a SRE in the human ABCD2 promoter and luciferase reporter constructs
  • Fig. 4 shows the direct ABCD2 induction by binding of SREBP
  • Fig. 5 and 6 show the induction of ABCD2 gene expression by H 2 0 2 and EtOH treatment; and Fig. 7 shows that ABCD2-deficiency results in increased cell death under conditions of oxidative stress.
  • ABCD2 gene expression is regulated by cholesterol in a SREBP-dependent manner: implications for a therapy of X-ALD
  • Lovastatin inhibits HMGCoA-reductase, the rate-limiting enzyme in cholesterol biosynthesis, thereby reducing cellular cholesterol.
  • human or mouse monocytes THP-1, WEHI-3
  • mouse mi- croglial cells BV-2
  • human X-ALD ABCDl deficient
  • healthy control fibroblasts were loaded and depleted by incubation with sterols, lipid-depleted medium or medium containing standard FCS for 2 days and quantified the ABCD2 mRNA level by real time RT-PCR (Fig. 1) .
  • ABCD2 expression is induced by SREBP - characterisation of a SRE in the ABCD2 promoter:
  • the luciferase activity clearly increased in a SREBP-dependent manner with both ABCD2 promoter constructs and with all three SREBP isoforms. Although the shorter promoter construct was somewhat less responsive, especially to SREBP2 , expression was still SREBP-inducible, strongly suggesting a proximal localisation of the sterol-regulatory element.
  • ABCD2 gene expression is induced by cholesterol-depletion using a mechanism requiring the maturation and binding of SREBPs. Consequently, the present invention provides a novel and unexpected pathway by which ABCD2 gene expression can be induced pharmacologically and thus provides a novel therapeutic approach for the development of a medication aimed to treat the severe disease X- ALD.
  • ABCD2 gene expression is induced under conditions of oxidative stress: implications for neurodegenerative disorders, e.g. Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis.
  • ABCD2 expression is induced when cells are treated with H 2 0 2 or ethanol, a condition resulting in oxidative stress.
  • the ABCD2 protein seems to play a role in cells facing oxidative stress, which is associated with diseases such as cancer and atherosclerosis but also major neurodegenerative and neuroin- flammatory disorders, e.g. Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis.
  • the upregulation of ABCD2 gene expression might also be important for other diseases than X-ALD.
  • ABCD2 gene expression is induced by ethanol or H 2 0 2 treatment:
  • ABCD2-deficiency results in increased cell death under conditions of oxidatve stress:
  • ABCD2 gene expression is induced under conditions of oxidative stress.
  • mouse primary ABCD2-defi- cient fibroblasts derived from an ABCD2 knock out mouse as well as wild type control fibroblasts were treated with different concentrations of H 2 0 2 and cell survival was assessed at different time points. After a two-hour treatment, cells lacking ABCD2 protein were more susceptible to cell death induced by oxidative stress when compared with the healthy controls (Fig. 7) .
  • ABCD2 unexpectedly has a role in cells facing oxidative stress.
  • induction of ABCD2 gene expression is not only favourable for X-ALD but also for other neurodegenerative disorders linked to oxidative stress, e.g. Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis.
  • the capacity of a compound to activate the SREBP pathway with yet unknown SREBP specificity may easily be tested by the methods available in the art as disclosed herein, especially e.g. the luciferase-based assay system.
  • Luciferase-based assay system for identification of compounds that stimulate ABCD2 expression in a SREBP-dependent manner:
  • ABCD2 gene expression is induced by SREBP through binding to a sterol regulatory element (SRE) located at -401/-391 (5 ' -AGCAGATGGCC-3 ' ) in the upstream ABCD2 promoter region.
  • SRE sterol regulatory element
  • oligonucleotides containing this sterol responsive region (5'- AGCTTGCAGATGGCCTGATTCGACCTCTCCG-3 ' and 5 '-GATCCGGAGAGGTCGAATCAG- GCCATCTGC-3 ' ) were annealed and cloned upstream of a beta-globin minimal promoter into a luciferase reporter construct to generate pGl-E21uc.
  • this plasmid is used to transiently transfect the immortalised human skin fibroblast cell line 1306 (ECACC number 90011887) .
  • the procedure of transfection is as follows: 40,000 human immortalised adult skin fibroblasts per well are plated into a 24- well plate and incubated overnight in DMEM medium supplemented with 10% fetal calf serum (typically containing at least 33 mg cholesterol per 100 ml) and 2 M L-glutamine.
  • cells are transfected using 1 ⁇ l lipofectamin 2000 reagent (Life Technology) , 0.5 ⁇ g pGl-E21uc or pGLuc, which is a construct containing the ⁇ -globin minimal promoter cloned in front of the luciferase gene but which does not contain the ABCD2 SRE-sequence, 0.1 ⁇ g of an expression plasmid encoding the human mature SREBPla or the empty vector, pCMV, as a negative control and 0.05 ⁇ g of the plasmid pCMV-beta-Gal to normalise the transfection efficiency.
  • a total amount of 0.65 ⁇ g DNA is used for each transfection.
  • the plasmids used for this lipofection have to be isolated from transformed XLl-Blue E.coli cells using the Endotoxin-free Maxi-Prep DNA isolation kit from Quiagen.
  • the transfection reaction is carried out for 3 hours according to the manufacturer's instructions in DMEM medium supplemented with 2 mM L-glutamine.
  • DMEM medium supplemented with 10% fetal calf serum (typically containing at least 33 mg cholesterol per 100 ml) , 2 mM L-glutamine, 50 U/ml penicillin and 100 ⁇ g/ml streptomycine for 24 h before addition of the putative SREBP-activating test substance to the medium.
  • Luciferase and beta-galactosidase activity is measured from 30 ⁇ l cell lysate using 50 ⁇ l Luciferase- ⁇ -Gal 1 step kit and 50 ⁇ l ⁇ -Gal trigger solution (Aureon Biosysterns, Vienna, Austria) or a comparable luciferase/ ⁇ -gal assay system according to the manufacturer's instructions and using a Mediators PhL luminometer (Aureon Biosys- tems) .
  • the reporter activity is obtained by calculating the ratio of luciferase and ⁇ -galactosidase activity.
  • the "x-fold induction by SREBPla” is obtained by comparing the induction obtained after cotransfection with the expression plasmids encoding the mature SREBPla isoform with the induction obtained after cotransfecting the empty vector pCMV.
  • the "x-fold induction by a SREBP activating compound" of a putative SREBP maturating compound is defined by its ability to induce reporter activity above the level that is obtained with the solvent of the SREBP maturing compound alone.
  • the following criteria define cell viability and transfection efficiency and thus, have to be fulfilled to declare a compound as being able to induce expression of pGl-E21uc and thus being able to induce ABCD2 gene expression in a SREBP-dependent manner.
  • the ratio of obtained luciferase and ⁇ -galactosidase activities of cells transfected with pGL-E21uc, the expression plasmid encoding mature human SREBPla and pCMV- ⁇ Gal should be above 1 . 5 .
  • the "x-fold induction by SREBPla” is the fold increase of the luciferase/ ⁇ -Gal ratio obtained after transfection of pGl- E21uc, the expression plasmid encoding mature human SREBPla, pCMV- ⁇ Gal compared with luciferase/ ⁇ -Gal ratio obtained from cells transfected with pGl-E21uc, pCMV, and pCMV- ⁇ Gal.
  • the fold SREBPla induction should be 50 fold.
  • x-fold induction by a SREBP activating compound is the fold increase of the luciferase/ ⁇ -Gal ratio obtained from cells transfected with pGl-E21uc, pCMV and pCMV- ⁇ Gal and treated for 24 h with the SREBP activating compound and the luciferase/ ⁇ -Gal ratio obtained from cells transfected with pGl-E21uc, pCMV and pCMV- ⁇ Gal and treated for 24 h with the solvent alone.
  • the reporter activity of the SREBP activating compound should be at least 2%, more preferred at least 3%, especially at least 5% of the reporter activity obtained after transfection with the plasmid encoding the mature SREBPla ("x-fold induction by SREBPla”) .
  • Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD) : implications for therapy. Hum Mol Genet 8, 907- 13. (1999) .
  • SREBPs Sterol regulatory element-binding proteins

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Abstract

L'invention concerne l'utilisation de composés activant le trajet de la protéine SREBP pour l'élaboration d'un médicament inducteur de protéine propre à l'adrénoleucodystrophie (ALDRP; ABCD2) chez les patients atteints de troubles neurodégénératifs ou neuro-inflammatoires, en particulier s'agissant de l'adrénoleucodystrophie liée à l'X.
PCT/EP2003/007504 2002-07-11 2003-07-11 Utilisation de composes activant le trajet de la proteine srebp WO2004006935A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006470A1 (fr) * 1993-08-30 1995-03-09 Merck & Co., Inc. Prevention et traitement de la maladie d'alzheimer
WO2000018394A1 (fr) * 1998-09-28 2000-04-06 The Johns Hopkins University Traitements de l'adreno-leucodystrophie et criblage de medicaments associes
WO2001006261A2 (fr) * 1999-07-17 2001-01-25 Glaxo Group Limited Competition de liaison d'antagonistes de la proteine d'activation de clivage de srebp (scap)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006470A1 (fr) * 1993-08-30 1995-03-09 Merck & Co., Inc. Prevention et traitement de la maladie d'alzheimer
WO2000018394A1 (fr) * 1998-09-28 2000-04-06 The Johns Hopkins University Traitements de l'adreno-leucodystrophie et criblage de medicaments associes
WO2001006261A2 (fr) * 1999-07-17 2001-01-25 Glaxo Group Limited Competition de liaison d'antagonistes de la proteine d'activation de clivage de srebp (scap)

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BROWN MS UND GOLDSTEIN JL: "The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor", CELL, CELL PRESS, CAMBRIDGE, NA, US, vol. 89, 2 May 1997 (1997-05-02), pages 331 - 340, XP002123067, ISSN: 0092-8674 *
GRAND-PERRET T ET AL: "SCAP ligands are potent new lipid-lowering drugs", NATURE MEDICINE 2001 UNITED STATES, vol. 7, no. 12, 2001, pages 1332 - 1338, XP002259713, ISSN: 1078-8956 *
JANOWSKI B A ET AL: "The hypocholesterolemic agent LY295427 reverses suppression of sterol regulatory element-binding protein processing mediated by oxysterols.", THE JOURNAL OF BIOLOGICAL CHEMISTRY. UNITED STATES 30 NOV 2001, vol. 276, no. 48, 30 November 2001 (2001-11-30), pages 45408 - 45416, XP002259712, ISSN: 0021-9258 *
PAHAN K ET AL: "Therapy for X-adrenoleukodystrophy: Normalization of very long chain fatty acids and inhibition of induction of cytokines by cAMP", JOURNAL OF LIPID RESEARCH 1998 UNITED STATES, vol. 39, no. 5, 1998, pages 1091 - 1100, XP002259711, ISSN: 0022-2275 *
PAI G SHASHIDHAR ET AL: "Lovastatin therapy for X-linked adrenoleukodystrophy: Clinical and biochemical observations on 12 patients", MOLECULAR GENETICS AND METABOLISM, vol. 69, no. 4, April 2000 (2000-04-01), pages 312 - 322, XP002259710, ISSN: 1096-7192 *
PUJOL A ET AL: "Characterization of the Adrenoleukodystrophy-Related (ALDR, ABCD2) Gene Promoter: Inductibility by Retinoic Acid and Forskolin", GENOMICS, ACADEMIC PRESS, SAN DIEGO, US, vol. 70, no. 1, 15 November 2000 (2000-11-15), pages 131 - 139, XP004437776, ISSN: 0888-7543 *
WEINHOFER ISABELLE ET AL: "Cholesterol regulates ABCD2 expression: Implications for the therapy of X-linked adrenoleukodystrophy", HUMAN MOLECULAR GENETICS, vol. 11, no. 22, 15 October 2002 (2002-10-15), pages 2701 - 2708, XP002259714, ISSN: 0964-6906 *

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