one with a scientific orientation

Transcription

LEUKOTREAT
2010 - 2013
Therapeutic strategies for leukodystrophies
www.leukotreat.eu
The research leading to these results has received funding from
the European Union Seventh Framework Programme ([FP7/2007-2013])
under grant agreement n°241622.
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TABLE OF CONTENT
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•
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•
•
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Summary………………………………………………..3
Workplan of the project………………………… 4
Key Results ……………………………………………. 5
The LeukoTreat Consortium……………………12
Dissemination & Integration…………………..54
Perspectives………………………………………….. 55
2
SUMMARY
7 studied leukodystrophies with known cause and
cellular/animal models
23 partners
€9 million budget
Innovative therapeutic strategies for
leukodystrophies
42 months
7 European countries
and Australia
19 research organisations
3
clinical data, mutation
data and biobank
Epidemiology
Natural history
Patients’ cohorts
WP3: Pharmacological
strategies to treat LDs
Cellular stress pathways
Modulation of specific gene
expression
Enzyme delivery to the brain
WP2:
Biomarkers for
LDs treatment
Diagnosis
Prognosis
WP7: Management
WP1*:
Characterizing LDs
for therapies
WP6: Dissemination
WP5: Ethical impacts of therapeutic challenges in LDs
WORKPLAN OF THE PROJECT
WP4: Innovative gene and
cell therapies in LDs
Combination of both therapies
New cell sources
Adaptation of new vector tools
* WP: WorkPackage (group of tasks to be performed)
4
KEY RESULTS
First Leukodystrophy Database
(> 1000 patients included)
11 preclinical trials
achieved
5 novel
clinical trials
4 confirmed or new biomarkers
First European LDs patients & families survey
More than 70 scientific publications
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1. Development of the first transnational patient database on leukodystrophies
(LeukoDataBase)
The LeukoDataBase developed by the LeukoTreat team includes today more than 1000 European patients and constitutes a unique
database on leukodystrophies in the world. The database centralises three categories of information, for each patient affected with
leukodystrophy: Clinical data, Biological Samples (existing biopsies from patients) and Mutation data (for each gene known to be
implicated in leukodystrophy). The LeukoDataBase allows a better understanding of the natural history of these diseases, their
evolution (number of patients, distribution, follow-up) and their genetic nature (mutation, how the disease is transmitted). In addition,
thanks to this new tool, it is now much easier to recruit patients for future therapeutic trials or to establish a more accurate and rapid
diagnosis of a specific subtype of LD, the ones determined by a known cause (with genetic markers such as PLP, GFAP, eIF2B and MLC1).
The LeukoDataBase is currently managed by ELA foundation (www.ela-asso.com).
Partners involved
Leader:
Ospedale Pediatrico Bambino GESU (Italy)
Dr. BERTINI Enrico, Dr. PIEMONTE Fiorella,
Dr. CARROZZO Rosalba, Dr. DENTICI Maria
Lisa
Université d’Auvergne Clermont Ferrand 1
(France)
Dr. VAURS BARRIERE Catherine, Dr. FOGLI
Anne, Dr. GUERROUI Samia, GONTHIER
Celine
Instituto Giannina Gaslini (Italy)
Dr. FILOCAMO Mirella, Dr. BIANCHERI
Roberta, Dr. ZARA Federico, Dr. REGIS
Stefano
Université Paris Diderot – Paris 7 (France)
Pr. BOESPFLUG-TANGUY Odile, Dr.
TONDUTI David, Dr. RENALDO Florence, Dr.
DORBOZ Imen, Dr MASLIAH Julien,
BARBIER Julie
Institut National de la Santé et de la
Recherche Médicale (France)
U986: Pr. AUOURG Patrick, Dr. SEVIN
Caroline
U676: Pr. RODRIGUEZ Diana, Dr. BURGLEN
Lydie
Fondazione IRCCS Istituto Neurologico
Carlo Besta (Italy)
Dr. UZIEL Graziella, Dr. GENETRINI Silvia
Universitaetsklinikum HamburgEppendorf (Germany)
Pr. KOHLSCHÜTTER Alfried, Dr BLEY
Annette
Eberhard Karls Universitaet Tuebingen
(Germany)
Pr. KRÄGELOH-MANN Ingeborg, BRAUN
Silke, GRÖSCHEL Samuel, KEHRER
Christiane
IT Development (data base)
Soluscience SA (France)
Dr. DANTAL Yann
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2. Identification & validation of LDs biomarkers
Biomarkers are key tools for monitoring treatments and also, as prognostic factors, for the optimization of therapeutic options. The
LeukoTreat research teams aimed at validating identified biomarkers and screening for new biomarkers:
 eIF2B was validated as a LD biomarker for the diagnosis of CACH/VWM disease using l-eIF2 (eIF2 from rat liver) in patients’
lymphoblasts. In addition, the utility of r-eIF2 (recombinant human eIF2 produced in yeast) as a diagnostic tool was demonstrated;
 N-acetylaspastate (NAA) and N-acetylaspartylglutamate (NAAG) were investigated as potential markers in hypomyelinating
leukodystrophy but their interest for therapeutic clinical trial needs further analysis ;
 The role of the oxidative stress in the axonal degeneration was investigated and an innovative lipidomics analysis was applied. It was
demonstrated that oxidative lesion markers are increased in MLD and PMD mice. In addition, 5 oxidized proteins in X-ALD mice spinal
cords were identified by redox proteomics. Biomarkers of oxidative damage were also identified in plasma of X-ALD patients and a
list of candidates for lipid biomarkers was established for X-ALD, MLD and PMD diseases.
Partners involved
Leader:
Fundació Institut d‘Investigació Biomèdica
de Bellvitge – IDIBELL (Spain)
Dr. PUJOL Aurora
(France)
Dr. FOGLI Anne, HUYGUE Aurélia
The University of Manchester (UK)
Pr. PAVITT Graham, Dr DE ALMEIDA
Rogerio
Academisch Medisch Centrum (The
Netherlands)
Pr. WANDERS Ronald, Dr. KULIK Wim
University of Cambridge (UK)
Dr. KARADOTTIR Ragnhildur Thora
Pr. BOESPFLUG-TANGUY Odile, Dr DORBOZ
Imen
University College London (UK)
Dr. ATTWELL David, Dr. BAKIRI Yamina,
ARANCIBIA-CARCAMO Irma Lorena
*CACH/VWM: Childhood Ataxia with Central Hypomyelination/ Vanishing White Matter; MLD: Metachromatic Leukodystrophy;
PMD: Pelizaeus-Merzbacher Disease; X-ALD: Adrenoleukodystrophy.
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3. Development of pharmacological strategies (1)
The LeukoTreat partners have designed rational pharmacological treatment by:
1. Screening molecules with neuroprotective or anti-oxidant/anti-inflammatory activities, able to clear misfolded proteins or to enhance
translation using in vitro and in vivo models of prototypic LDs:
• The potential therapeutic effect of a cholesterol-derivative, the olesoxime, was tested in the PLP-overexpressing mice models of PMD
(+PlpTg) and the axonopathy observed in the PLP null mice models of SPG2 (Plp null). While for +PlpTg no tremendous treatment
effects was observed, positive effects could be observed in Plp null mice leading to a third in vivo study which is under process;
• The efficacy of the dietary supplement Turmeric in different mouse models of PMD was evaluated. With Turmeric, it was possible to
considerably improve the pathology of PLPoverexpressor mouse model and mortality of PLPrumpshaker mice was considerably delayed. A
future therapy trial using a Curcumin preparation with improved bioavailability (Meriva-Curcumin) is planned.
• A proof-of-concept clinical trial showed that oxidative stress is a main causative factor underlying axonal degeneration in X-ALD. In
addition, a related human clinical trial for X-ALD has been completed in 2013 and is under analysis;
2. Targeting modulation of specific gene expression or enzyme replacement using preclinical therapy trials in exact animal models for
LDs:
• Pharmacological strategies to treat Alexander disease were evaluated. Several selected compounds lead to a significant decrease of
aggregate-bearing astrocytes but for some of them the decrease is associated with modifications suggesting a toxic effect.
• Bezafibrate was identified as the top molecule for lowering VLCFA levels in X-ALD fibroblasts and a proof-of-concept clinical trial was
initiated to evaluate its effects on X-ALD patients. Unfortunately, bezafibrate appears to have no therapeutic utility in X-ALD.
• The efficacy of top eIF2-enhancing compounds in eIF2B5 mutated patients fibroblasts or lymphoblasts was evaluated with mixed
results.
• The pharmacological induction of the ABCD2 gene as a potential treatment for X-ALD was investigated. Compounds that can be
suggested for a therapeutic induction were identified and the validity of ABCD2 up-regulation as a potential therapeutic target in XALD was supported.
• The results of a therapy trial regarding the efficacy of a progesterone antagonist (Lonaprisan) in PLPoverexpressor mice were evaluated.
The study suggests that the progesterone receptor may constitute a druggable target for a rational therapy for PMD patients
harbouring Plp1 gene duplications.
• A proof-of-concept clinical trial showed that intracerebroventricular infusion of enzymatically active ARSA corrects central nervous
system pathology and dysfunction in a mouse model of MLD. This success contributed to the implementation of a phase I/II clinical
trial for children with MLD.
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3. Development of pharmacological strategies (2)
Partners involved
Leader:
Max Planck Gesellschaft zür Förderung der
Wissenschaften (Germany)
Dr. WERNER Hauke, Dr. NAVE Klaus-Armin,
Dr. SEREDA Michael
(France)
Dr FOGLI Anne, Dr. BEGOU Melina, DEPIETS
PETIT Bérengère, DIOT Céline
Universitaetsklinikum Bonn (Germany)
Pr. GIESELMANN Volkmar, Dr. MATZNER
Ulrich, GERLACH Debora
U676: Pr RODRIGUEZ Diana
The University of Manchester (UK)
Pr. PAVITT Graham, Dr. CALLAN Hayley
Fundació Institut d‘Investigació Biomèdica
de Bellvitge – IDIBELL (Spain)
Dr. PUJOL Aurora
Medizinische Universitaet Wien (Austria)
Pr. BERGER Johannes, Dr. FORSS-PETTER
Sonja, HABERL Manuela, WIESINGER
Christoph, EINWICH Angelika
Academisch Medisch Centrum (The
Netherlands)
Pr. WANDERS Ronald, Dr. KEMP Stephan,
SCHACKMANN Martin
Pr. BOESPFLUG-TANGUY Odile
Trophos SA (France)
Dr. BORDET Thierry, Dr. MICHAUD Magali,
CHAIMBAULT Corinne, AFXANTIDIS Jean,
LONSKI Priska, HOCINE Mélanie,
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4. Development of gene & cell therapies
The LeukoTreat research teams have developed innovative approaches :
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An hematopoietic stem cell (HSC) transplantation using lentiviral vector to deliver “therapeutic” proteins to the brain was performed
as a phase I/II clinical trial. The results provide (a) good safety profile and the proof-of-principle of a novel gene therapy approach
allowing expression of therapeutic protein in brain microglia; (b) new treatment options for ALD and MLD patients with less risks
than currently available therapies (allogeneic HSC transplantation) and (c) pre-clinical proof-of-concept in mice in GLD and
Canavan disease;
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It was also shown that HSC transplantation is a potential therapeutic strategy for X-ALD;
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It was demonstrated that cell therapy is particularly attractive for LDs using neural stem cell (NSCs) transplantation;
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A proof-of principle was established for neonatal transplantation of GALC-overexpressing Neural Stem Cells (NSCs) in GLD and MLD
mice;
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A proof-of principle was established for neonatal transplantation of normal NSCs in PLP overexpressing mice for severe PMD
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The feasibility and efficacy of a combined strategy based on neural stem cell transplant and bone marrow transplant in a GLD mouse
model was shown;
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The feasibility of direct gene delivery to the brain has been tested in two distinct LDs models: a proof of efficiency and safety of
intracerebral delivery of AAV-ARSA has been established in MLD mice and non-human primates while a proof-of-concept was made
in mouse model of Canavan;
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A phase I/II trial of intracerebral gene therapy for MLD is now open for recruitment
Partners involved
Leader:
U986: Pr. AUBOURG Patrick, Dr. CARTIER
Nathalie, Dr. SEVIN Caroline, DUFAYETCHAFFAUD Gaëlle, Dr. GUIDOUX Sylvie,
FOUQUET Françoise, Dr. GAUTIER Benoit
U975: Dr. BARON-VAN EVERCOOREN Anne,
NAIT-OUMESMAR
Brahim,
BACHELIN
Corinne, DEBOUX Cyrille, MARTEYN
Antoine
(France)
Dr. BEGOU Melina, GONTHIER Céline
Universitaetsklinikum Bonn (Germany)
Pr. GIESELMANN Volkmar, Dr. MATZNER
Ulrich, STEIN Axel
Medizinische Universitaet Wien (Austria)
Pr. BERGER Johannes
Fondazione Centro San Raffaele (Italy)
Dr. BIFFI Alessandra, Dr. GRITTI Angela
Pr. BOESPFLUG-TANGUY Odile
University of New South Wales (Australia)
Dr. KLUGMANN Matthias, KLUGMANN
Claudia, TEAHAN Oria, JONQUIERES Georg
*GLD: Globoid Cell Leukodystrophy / Krabbe Disease
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5. Patients & families’ issues
The project’s Ethics Committee and Ethics Research Group coordinated by Université Paris Descartes have created an innovative
Database Charter, harmonized Patient Information & Consent Forms and a Patient Leaflet for an enhanced communication with the
patients and their families regarding patient database (LeukoDataBase – see result 1) participation and an optimal protection of the
patients’ rights. These documents have been created in the specific framework of the LeukoTreat project but are available as models for
a broader use on www.leukotreat.eu.
The Ethics Research Group also conducted a European survey in five languages to evaluate the expectations of patients and their
families regarding research in LDs - particularly as regard to data sharing in the LeukoTreat database - and to study how patients may
produce a useful knowledge for scientific purpose (publication in preparation). The survey shows a strong adhesion of patients/families
to participate to the LeukoDataBase. Their main motivation is research progress in order to improve treatments and access to clinical
trials. The study provides insight into the conditions which are essential in their view concerning datasharing. Being kept informed fully
and regularly is one major expectation.
Partners involved
Leader:
Université Paris Descartes - LEM (France)
Dr. MOUTEL Grégoire, Dr. DUCHANGE
Nathalie, Dr. CALLIES Ingrid, Dr. DARQUY
Sylviane, LECLERCQ Thomas, LOEVE Boris,
D’AUDIFFRET Diane, LAPOINTE AnneSophie
Pr. BOESPFLUG-TANGUY Odile, VENDEVILLE
Marie-Louise
Soluscience SA (France) et Université
d’Auvergne Clermont Ferrand 1 (France)
Dr. DANTAL Yann, Dr. GUERROUI Samia
European Association against
leukodystrophies – ELA (France)
ALBA Guy, FAVEAUX Philippe, DURAN
Marie-Josée, BLONDEAU Marie-Claude
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THE LEUKOTREAT CONSORTIUM
19 RESEARCH ORGANISATIONS
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Coordinator: UNIVERSITE D'AUVERGNE CLERMONT-FERRAND 1
(France)
OSPEDALE PEDIATRICO BAMBINO GESU (Italy)
ISTITUTO GIANNINA GASLINI (Italy)
UNIVERSITAETSKLINIKUM BONN (Germany)
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
(France)
THE UNIVERSITY OF MANCHESTER (UK)
FUNDACIO INSTITUT D’INVESTIGACIO BIOMEDICA DE BELLVITGE
(Spain)
MAX PLANCK GESELLSCHAFT ZUR FORDERUNG DER
WISSENSCHAFTEN E.V. (Germany)
MEDIZINISCHE UNIVERSITAET WIEN (Austria)
UNIVERSITY COLLEGE LONDON (UK)
FONDAZIONE CENTRO SAN RAFFAELE (Italy)
ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN
AMSTERDAM (The Netherlands)
UNIVERSITE PARIS DESCARTES (France)
UNIVERSITY OF CAMBRIDGE (UK)
UNIVERSITE PARIS DIDEROT – PARIS 7 (France)
FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA (Italy)
UNIVERSITAETSKLINIKUM HAMBURG – EPPENDORF (Germany)
EBERHARD KARLS UNIVERSITAET TUEBINGEN (Germany)
UNIVERSITY OF NEW SOUTH WALES (Australia)
3 SMES
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TROPHOS SA (France)
SOLUSCIENCE SA (France)
FRANCE EUROPE INNOVATION
(France)
1 PATIENT
ASSOCIATION

EUROPEAN ASSOCIATION
AGAINST LEUKODYSTROPHIES
(ELA)
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 THE UNIVERSITY OF CLERMONT FERRAND 1 (FRANCE)
THE RESEARCH UNIT
The Research Unit “Genetic Reproduction and Development” (supported by the CNRS (U6247) and INSERM (U931)) aims at studying glial cell
interactions during normal and pathological development of CNS.
The department coordinates the reference center for leukodystrophies in France, taking care of patients and providing molecular diagnosis of LDs
with a genetic marker. A biobank including samples from more than 1200 LDs affected families has been established and enriched through the
national LeukoFrance network. Glial cell interactions are studied via the analysis of physiopathological mechanisms implicated in hypomyelinating
and vacuolating LDs using patients’ samples (tissues, biological fluids, cells) and animal models.
LeukoTreat Team: Pr. VAURS BARRIERE Catherine, Dr. BEGOU Melina, DEPIETS PETIT Bérengère, Pr. FOGLI Anne, HUYGUE Aurélia, GONTHIER
Céline, Dr. GUERROUI Samia, DIOT Céline
ROLE IN THE PROJECT
 Pr. VAURS BARRIERE Catherine: WP1 Co-leader: Supervise the biobank and mutation databases. In charge of PLP1 mutation study
 Dr. BEGOU Melina with DEPIETS PETIT Bérengère: WP3: Study of efficacy of the chosen TROPHOS molecule (olesoxime) in PLOA and PLP null
mouse models of PLP-pathies; WP3 : histological analysis of the treatment; WP4: Study of therapeutic potential of NSC graft in PLOA transgenic
mice
 Pr. FOGLI Anne with HUYGUE Aurélia: WP1&WP2: study of EIF2B mutations and EIF2B activity in fibroblasts and lymphoblasts; WP3: test on
human mutated cells the effects of protein translation regulators
 GONTHIER Céline: WP4: development of the in vitro evaluation of the morpholino efficacy
 Dr. GUERROUI Samia: WP1: development of the LD European database with Soluscience and of bioinformatics tools in order to enter data and to
interconnect the European existing data bases
 DIOT Céline: WP3 and WP4: involved 1) in the breeding and genotyping of mice used in the different protocols; 2) in the post mortem evaluation
of the efficacy of the treatment at the level of the mRNA (qRT-PCR) or the protein (western blot and immunohistochemestry);
* See the Workplan for the Work Packages (WPs) description
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PUBLICATIONS (acknowledged LEUKOTREAT GRANT)
• Boespflug-Tanguy, O., Aubourg, P., Dorboz, I., Bégou, M., Giraud, G., Sarret, C., Vaurs-Barrière, C. (2011) Neurodegenerative disorder related
to AIMP1/p43 mutation is not a PMLD. Am J Hum Genet. 2011 Mar 11; 88(3):392-93; author reply 393-95.
• Grossi, S., Regis, S., Biancheri, R., Mort, M., Lualdi, S., Bertini, E., Uziel, G., Boespflug-Tanguy, O., Simonati, A., Corsolini, F., Demir, E.,
Marchiani, V., Percesepe, A., Stanzial, F., Rossi, A., Vaurs-Barrière, C., Cooper, D.N., Filocamo, M. (2011) Molecular Genetic Analysis of the PLP1
Gene in 38 Families with PLP1-related disorders: Identification and Functional Characterization of 11 Novel PLP1 Mutations. Orphanet Journal of
Rare Dis. 2011 Jun 16; 6(1):40.
• Carra-Dalliere, C., Horzinski, L., Ayrignac, X., Vukusic, S., Rodriguez, D., Mauguiere, F., Peter, L., Goizet, C., Bouhour, F., Denier, C., Confavreux,
C., Obadia, M., Blanc, F., de Seze, J., Guennoc, A.M., Sartori, E., Laplaud, D., Antoine, J.C., Fogli, A., Boespflug-Tanguy, O., Labauge, P. (2011)
Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases. Rev Neurol (Paris). 2011 Nov; 167(11):802-11.
• Sarret, C., Rigal, M., Vaurs-Barrière, C., Dorbiz, I., Eymard-Pierre, E., Combes, P., Giraud, G., Wanders, R.J., Afenjar, A., Francannet, C.,
Boesplug-Tanguy, O. (2012) Sjögren-Larsson syndrome: novel mutations in the ALDH3A2 gene in a French cohort. J Neurol Sci. 2012 Jan 15;
312(1-2):123-6.
• Combes, P., Kammoun, N., Monnier, A., Gonthier-Guéret, C., Giraud, G., Bertini, E., Chahnez, T., Fakhfakh, F., Boespflug-Tanguy, O, VaursBarrière, C. (2012) Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. Ann Neurol. 2012 Jan; 71(1):146-48.
• Combes, P., Planche, V., Eymard-Pierre, E., Sarret, C., Rodriguez, D., Boesplug-Tanguy, O., Vaurs-Barrière, C. (2012) Relevance of SOX17
Variants for Hypomyelinating Leukodystrophies and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Ann Hum Genet. 2012 May;
76(3):261-267.
• Huyghe, A., Horzinski, L., Hénaut, A., Gaillard, M., Bertini, E., Schiffmann, R., Rodriguez, D., Dantal, Y., Boespflug-Tanguy, O., Fogli, A. (2012)
Developmental Splicing Deregulation in Leukodystrophies related to EIF2B Mutations. PLoS One. 2012 Jun; 7(6):e38264.
• Fogli, A., Merle, C., Roussel, V., Schiffmann, R., Ughetto, S., Theisen, M., Boespflug-Tanguy, O. (2012) CSF N-Glycan Profiles to Investigate
Biomarkers in Brain Developmental Disorders: Application to Leukodystrophies Related to eIF2B Mutations. PLoS One. 2012 Aug;7(8):e42688.
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• De Almeida, R., Fogli, A., Gaillard, M., Scheper, G.C., Boespflug-Tanguy, O., Pavitt, G.D. (2013) A Yeast Purification System for Human
Translation Initiation Factors eIF2 and eIF2BƐ and Their Use in the Diagnosis of CACH/VWM Disease. PLosOne. 2013 Jan 15; 8(1):e53958.
• Petit B, Giraudet F, Béchon C, Bardin L, Avan P, Boespflug-Tanguy O, Bégou M (2014) Mice with a deletion of the major central myelin protein
exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization. Neurobiol Dis. 2014 May;65:55-68.
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 OSPEDALE PEDIATRICO BAMBINO GESU (ITALY)
THE LABORATORY
The Laboratory of Molecular Medicine (UMM) of OSPEDALE PEDIATRICO BAMBINO GESU is a national referring center in Italy for a large number of
pediatric diseases, including muscular and neuro-degenerative disorders, and inherited leukodystrophies.
The UMM was actively involved in a FP6-TREAT-NMD European project to organize trials for patients with Spinal Muscular Atrophy (SMA). UMM is a
European referring center for molecular diagnosis of several rare disorders including the megalencephalic leukodystrophy with subcortical cysts
(MLC). UMM is also involved in clinical activity in collaboration with the Division of Pediatric Neurology, organizing about 2100 clinical
observations/year for physical therapy.
LeukoTreat Team: Dr. BERTINI Enrico, Dr. SANTORELLI Filippo, Dr. PIEMONTE Fiorella, Dr. CARROZZO Rosalba, Dr. DENTICI Maria Lisa
ROLE IN THE PROJECT
 Dr. BERTINI Enrico: WP1 leader. Supervision of the clinical manager for south Europe with expertise in imaging. Clinical and genetic definition of
a new form of inherited leukodystrophies
 Dr. SANTORELLI Filippo: Study of MLC1 mutations. Molecular genetics study of a new form of demyelination leukodystrophy
 Dr. PIEMONTE Fiorella: WP1: collecting patient with lysomal LDs and with mitochondrial respiratory chain defect
 Dr. CARROZZO Rosalba: WP1: biobanking of biological material from patients with LDs
 Dr. DENTICI Maria Lisa: WP1: clinical data manager
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 OSPEDALE PEDIATRICO BAMBINO GESU (ITALY)
 Grossi S., Regis S., Biancheri R., Mort M., Lualdi S., Bertini E., Uziel G., Boespflug-Tanguy O., Simonati A., Corsolini F., Demir E., Marchiani V.,
Percesepe A., Stanzial F., Rossi A., Vaurs-Barrière C., Cooper D.N., Filocamo M. (2011) Molecular Genetic Analysis of the PLP1 Gene in 38
Families with PLP1-related disorders: Identification and Functional Characterization of 11 Novel PLP1 Mutations. Orphanet Journal of Rare Dis.
2011 Jun 16; 6(1):40
 Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM,
Bacino CA, Battini R, Bertini E, Brogan PA, Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I, Fazzi E, Garcia-Cazorla A,
Heiberg A, Kawaguchi M, Kumar R, Lin JP, Lourenco CM, Male AM, Marques W Jr, Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen M,
Robinson RA, Rozenberg F, Schmidt JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling EL, Wassmer E, Whittaker E,
Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP, O'Connell MA, Lovell SC, Crow YJ. Mutations in ADAR1 cause Aicardi-Goutières
syndrome associated with a type I interferon signature. Nat Genet. 2012 Nov;44(11):1243-8.
 Combes P, Kammoun N, Monnier A, Gonthier-Guéret C, Giraud G, Bertini E, Chahnez T, Fakhfakh F, Boespflug-Tanguy O, Vaurs-Barrière C.
(2012) Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. Ann Neurol. 2012 Jan;71(1):146-8. doi: 10.1002/ana.22295.
 Lanciotti, A., Brignone, M.S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T.C., Ambrosini, E.
(2012) Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionnally cooperates with the TRPV4 cation channel to activate
the response of astrocytes to osmotic stress: dysregulation by pathological mutations. Hum Mol Genet. 2012 May 15; 21(10):2166-80.
 Huyghe A, Horzinski L, Hénaut A, Gaillard M, Bertini E, Schiffmann R, Rodriguez D, Dantal Y, Boespflug-Tanguy O, Fogli A. (2012)
Developmental Splicing Deregulation in Leukodystrophies Related to EIF2B Mutations. PLoS One. 2012 Jun;7(6):e38264
 Petrillo S, Piemonte F, Pastore A, Tozzi G, Aiello C, Pujol A, Cappa M, Bertini E. Glutathione imbalance in patients with X-linked
adrenoleukodystrophy. Mol Genet Metab. 2013 May 22. pii: S1096-7192(13)00175-3. doi: 10.1016/j.ymgme.2013.05.009.
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 ISTITUTO GIANNINA GASLINI (ITALY)
THE INSTITUTE
Giannina Gaslini Institute is the biggest paediatric hospital in Italy. It comprises 22 clinical units including all paediatric specialties. Gaslini ranks first
among pediatric Ministry of Health-funded research Institutes and among the top five of the over 40 Ministry of Health-funded research Institutes.
The institute has already conducted FP6/FP7 projects no.037315 – EPICURE; TRAPS no. 200923; CURE HLH no. 201461; TRIPR no. 046108.
LeukoTreat Team: Dr. FILOCAMO Mirella, Dr. BIANCHERI Roberta, Dr. ZARA Federico, Dr. STEFANO Regis
ROLE IN THE PROJECT
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Dr. FILOCAMO Mirella: WP1: Supervision of the Biobank/mutation manager for Southern Europe
Dr. BIANCHERI Roberta: WP1: Natural history
Dr. ZARA Federico: WP1: Selection patients (molecular diagnosis)
Dr. STEFANO Regis: WP1: Selection patients (molecular diagnosis)
 Grossi S, Regis S, Biancheri R, Mort M, Lualdi S, Bertini E, Uziel G, Boespflug-Tanguy O, Simonati A, Corsolini F, Demir E, Marchiani V,
Percesepe A, Stanzial F, Rossi A, Vaurs-Barrière C, Cooper DN, Filocamo M. Molecular genetic analysis of the PLP1 gene in 38 families with PLP1related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis. 2011 Jun 16;6:40.
 Biancheri R, Rosano C, Denegri L, Lamantea E, Pinto F, Lanza F, Severino M, Filocamo M. (2012) Expanded spectrum of Pelizaeus-Merzbacherlike disease: literature revision and description of a novel GJC2 mutation in an unusually severe form. Eur J Hum Genet. 2012 Jun; Epub ahead of
print
 Regis S., Corsolini F., Grossi S., Tappino B., Cooper D.N., Filocamo M. (2013) Restoration of the normal splicing pattern of the PLP1 gene by
means of an antisense oligonucleotide directed against an exonic mutation. PlosOne; 8(9):e73633
 Siri L, Rossi A, Lanza F, Mazzotti R, Costa A, Stroppiano M, Gaiero A, Cohen A, Biancheri R, Filocamo M. A novel homozygous splicing mutation
in PSAP gene causes metachromatic leukodystrophy in two Moroccan brothers. Neurogenetics. 2014 Jan 31. [Epub ahead of print] PubMed
PMID: 24478108.
 Lorioli L, Cesani M, Regis S, Morena F, Grossi S, Fumagalli F, Acquati S, Redaelli D, Pini A, Sessa M, Martino S, Filocamo M, Biffi A. Critical issues
for the proper diagnosis of Metachromatic Leukodystrophy. Gene. 2014, 537(2):348-51. doi: 10.1016
18
 UNIVERSITAETSKLINIKUM BONN (GERMANY)
THE RESEARCH UNIT
UKB (UNIVERSITAETSKLINIKUM BONN) is the University Hospital of the Medical Faculty of the Friedrich-Wilhelms-Universität Bonn. It owns a
research unit of Biochemistry and Molecular Biology which has longstanding record in research on lysosomal leukodystrophies. The research unit is
well equipped with laboratory and cell culture facilities, animal housing, MALDI TOF mass spectrometer, LC-MS/MS ion trap spectrometer, real time
PCR cycler, various HPLC and FPLC units for protein purification, and a single molecule microscopy unit. The unit has access to laser scan microscopy,
cell sorting and microarray platforms.
LeukoTreat Team: Pr. GIESELMANN Volkmar, Dr. MATZNER Ulrich, STEIN Axel, GERLACH Debora
ROLE IN THE PROJECT
 Pr. GIESELMANN Volkmar, GERLACH Debora, STEIN Axel and Dr. MATZNER Ulrich : WP3: Enzyme replacement trials in MLD mice; WP4:
Biochemical background of transfer of lysosomal enzymes between microglia, oligodendrocytes and neurons
 Stroobants S, Gerlach D, Matthes F, Hartmann D, Fogh J, Gieselmann V, D'Hooge R, Matzner U (2011) Intracerebroventricular enzyme infusion
corrects central nervous system pathology and dysfunction in a mouse model of metachromatic leukodystrophy. Hum Mol Genet.
2011;20(14):2760-69
 Kehrer C, Blumenstock G, Gieselmann V, Krägeloh-Mann I, on behalf of the German Leukonet. (2011) The natural course of gross motor
deterioration in metachromatic leucodystrophie. Dev Med Child Neurol. 2011 Sep;53(9):850-5. doi: 10.1111/j.1469-8749.2011.04028.x. Epub
2011 Jun 27
 Gieselmann V, Krägeloh-Mann I. Metachromatic Leukodystrophy. In: Raymond G, Eichler F Fatemi A, Naidu S (Ed.) “Leukodystrophies”, Mac
Keith Press, London, 2011, p. 130-155
 Krägeloh-Mann I; Kehrer C; Gieselmann V. Metachromatic leukodystrophy – what is new? Padiatr Croat 2012; 56:115-118
 Gieselmann V, Wenger D, Krägeloh-Mann I. Metachromatic Leukodystrophy and Globoid Cell Leukodystrophy. In: Mehta A, Winchester B (Ed.),
Lysosomal Storage Disorders. John Wiley & Sons, 2012, p. 70-79
19
 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
(FRANCE)
THE RESEARCH UNIT
Team Patrick AUBOURG
UMR745 (Genetics and Biotherapy of Neurodegenerative and Proliferative diseases of the Nervous System) is a mixed INSERM-University Paris
Descartes research unit that pursues the development of therapeutic strategies to fight several hereditary diseases of the nervous system. In
respect to leukodystrophies, this research unit develops in an integrative way: 1) Therapeutic strategies in adrenoleukodystrophy and
metachromatic leukodystrophy based on "ex vivo" or "in vivo" gene transfer that can be implemented in clinics which are main topics of WP4.; 2)
Genomic approaches to study complex genotype-phenotype relationships that modify the clinical presentation of ALD.
LeukoTreat Team: Pr. AUOURG Patrick, Dr. CARTIER Nathalie, Dr. SEVIN Caroline, VARIN Jennifer, DUFAYET-CHAFFAUD Gaëlle, Dr. GUIDOUX
Sylvie, FOUQUET Françoise, Dr. GAUTIER Benoit, BARBIER Mathieu
ROLE IN THE PROJECT
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Pr. AUBOURG Patrick: WP1: Responsible for the ALD, MLD LeukoFrance DB; WP2: Genomic polymorphic markers for X-ALD pronostic,
experience in human genetics and molecular biology; WP4: WP leader
Dr. CARTIER Nathalie: WP4: Responsible for the evaluation of the efficacy and safety of HSC gene therapy using LV and co-responsible for
understanding the mechanisms of disease correction by microglia in the LD brain
Dr. SEVIN Caroline: WP1: ALD, MLD LeukoFrance DB; WP4: co-responsible for the intracerebral delivery of AAV vector: safety and vector
diffusion in non-human primates and the development of AAV-based vectors with glial tropism
VARIN Jennifer: WP2: Genomic polymorphic markers for X-ALD pronostic
DUFAYET-CHAFFAUD Gaëlle: WP4: Technical accomplishment of the evaluation of the efficacy and safety of HSC gene therapy using LV
Dr. GUIDOUX Sylvie: WP2: Genomic polymorphic markers for X-ALD pronostic
FOUQUET Françoise: WP4: Technical accomplishment for the tasks ‘intracerebral delivery of AAV vector: safety and vector diffusion in nonhuman primates’ and ‘the development of AAV-based vectors with glial tropism’
Dr. GAUTIER Benoit: WP4: Co-responsible under the direction of Dr. Sevin for the tasks ‘intracerebral delivery of AAV vector: safety and vector
diffusion in non-human primates’ and ‘the development of AAV-based vectors with glial tropism
BARBIER Mathieu: WP2: Genomic polymorphic markers for X-ALD pronostic
20
(FRANCE)
 Fourcade S., Ruiz M., Guilera C., Hahnen E., Brichta L., Naudi A., Portero-Otín M., Dacremont G., Cartier N., Wanders R., Kemp S., Mandel JM.,
Wirth B., Pamplona R., Aubourg P., Pujol A. (2010) Valproic acid induces antioxidant effects in X-ALD. Human Molecular Genetics 19(10): 200514
 Boespflug-Tanguy, O., Aubourg, P., Dorboz, I., Bégou, M., Giraud, G., Sarret, C., Vaurs-Barrière, C. (2011) Neurodegenerative disorder related
to AIMP1/p43 mutation is not a PMLD. Am J Hum Genet. 2011 Mar 11; 88(3):392-93; author reply 393-95
 Biffi A, Aubourg P, Cartier N. (2011) Gene therapy for leukodystrophies. Hum Mol Genet. 2011 Apr;20(R1):R42-R53
 Barbier, M., Sabbagh, A., Kasper, E., Asheuer, M., Ahouansou, O., Pribill, I., Forss-Petter, S., Vidaud, M., Berger, J., Aubourg, P. (2012) CD1
Gene Polymorphisms and Phenotypic Variability in X-Linked Adrenoleukodystrophy. PLos One 2012 Jan; 7(1):e29872.
 Schlüter, A., Espinosa, L., Fourcade, S., Galino, J., Lopez, E., Ilieva, E., Morato, L., Asheuer, M., Cook, T., McLaren, A., Reid, J., Kelly, F., Bates,
S., Aubourg, P., Galea, E., Pujol, A. (2012) Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy.
Hum Mol. Genet. 2012 Mar 1; 21(5):1062-77
 Piguet, F., Sondhi, D., Piraud, M., Fouquet, F., Hackett, N.R., Ahouansou, O., Vanier, M.T., Bieche, I., Aubourg, P., Crystal, R.G., Cartier, N.,
Sevin, C. (2012) Correction of Brain Oligodendrocytes by AAVrh.10 Intracerebral Gene Therapy in Metachromatic Leukodystrophy Mice. Human
Gene Therapy. 2012 Aug;23(8):903-14
 Kemp S, Berger J, Aubourg P. (2012) X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects. BBA-Mol Basis
Dis. 1822(9):1465-74
 Galea E, Launay N, Portero-Otin M, Ruiz M, Pamplona R, Aubourg P, Ferrer I, Pujol A*. (2012) Oxidative stress underlying axonal degeneration
in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta. Sep 12;1822(9):1475-88
 Martin A, Sevin C, Lazarus C, Bellesme C, Aubourg P, Adamsbaum C. (2012) Toward a Better Understanding of Brain Lesions during
Metachromatic Leukodystrophy Evolution. AJNR Am J Neuroradiol. 2012 Oct;33(9):1731-9
21
(FRANCE)
 Arens A, Appelt JU, Bartholomae C, Gabriel R, Paruzynski A, Gustafson D, Cartier N, Aubourg P, Deichmann A, Glimm H, von Kalle C, Schmidt
M. Bioinformatical Clonality Analysis of Next Generation Sequencing Derived Viral Vector Integration Sites, Hum Gene Ther Methods. 2012 Jun
29 [Epub ahead of print]
 Debs R, Froissart R, Aubourg P, Papeix C, Douillard C, Degos B, Fontaine B, Audoin B, Lacour A, Said G, Vanier MT, Sedel F. Krabbe disease in
adults: phenotypic and genotypic update from a series of 11 cases and a review, J Inherit Metab Dis. 2012 Nov 30
 Aubourg P, Wanders R. Peroxisomal disorders, Handb Clin Neurol. 2013;113:1593-609.
 Morató L., Galino J., Ruiz M., Calingasan N.Y., Starkov A.A., Dumont M., Naudí A., Martínez J.J., Aubourg P., Portero-Otín M., Pamplona R.,
Galea E., Beal M.F., Ferrer I., Fourcade S., Pujol A. (2013) Pioglitazone halts axonal degeneration in a mouse model of X-linked
adrenoleukodystrophy. Brain 2013 Jun 22; Epub ahead of print
22
(FRANCE)
THE RESEARCH UNIT
Team Anne Baron-Van Evercooren
The Baron-Van Evercooren lab has made important contributions to the understanding of remyelination in the CNS and the development of
therapeutic approaches to promote remyelination. Through the use of skills in cell culture, animal models of demyelination and transplantation
paradigms, the lab has 1) defined the contribution of adult neural stem cells to oligodendrogenesis during myelin repair, 2) developed models of
demyelination in primates, 3) substantially contributed to establish the role of CNS and PNS myelin-forming cells and their stem cells in
remyelination.
LeukoTreat Team: Dr. BARON-VAN EVERCOOREN Anne, NAIT-OUMESMAR Brahim, BACHELIN Corinne, DEBOUX Cyrille, MARTEYN Antoine
ROLE IN THE PROJECT
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Dr. BARON-VAN EVERCOOREN Anne: WP4: Development of the human stem cell therapy approach in animal models of LD and explore the
potential of this strategy alone or in combination with pro-myelinating factors
NAIT-OUMESMAR Brahim: WP4: Transcriptional profile of the huNPCs before and after transplantation
BACHELIN Corinne: WP4: Ultrastructural characterization of huNPC in vivo
DEBOUX Cyrille: WP4: Production and characterization of huNPC in vitro
MARTEYN Antoine: WP4
PUBLICATIONS (LEUKOTREAT GRANT)
 Buchet D, Garcia C, Deboux C, Nait-Oumesmar B, Baron A. (2011) Human neural progenitors from different foetal forebrain regions
remyelinate the adult mouse spinal cord. Brain 2011;134(4):1168-83
 Matsas R. and Baron-Van Evercooren A. (2013) Glial cell transplantation, in Neuroglia, Section 3. Role of Glial cells in disease, Recovery of
neural functions by H. Kettenman and B. Ramson, Ed Oxford University Press.
23
(FRANCE)
THE RESEARCH UNIT
Team Danielle PHAM DINH
The interests of this INSERM team focused on studies of myelin genes and corresponding pathologies; the team is constantly involved in
clinic/research interactions. This team characterized several myelin- and oligodendrocyte-specific genes (PLP, PO, MOG), and seek for implication of
these genes in genetic dys- / demyelinating diseases such as Pelizaeus-Merzbacher disease, Charcot-Marie-Tooth disease, and Multiple sclerosis.
They are now studying the pathophysiological mechanisms involved in new leukodystrophies whose originality relies in that the primary target cell is
the astrocyte, particularly Alexander disease (AXD).
LeukoTreat Team: Dr. PHAM DINH Danielle, Pr. RODRIGUEZ Diana, Dr. MIGNOT Cyril, DUBIEF Emeline
ROLE IN THE PROJECT
 Dr. PHAM DINH Danielle: WP2: Role of astrocytes in GFAP related disorders studying KI GFAP mice; WP3: Pharmacological release of GFAP in
AXD using reliable cell culture model which permits the evaluation of selected compounds modulating pathways involved in the refolding of
abnormally folded proteins
 Pr. RODRIGUEZ Diana: WP1: Clinical expertise for patients from the LeukoFrance network; WP2: Role of astrocytes GFAP related disorders
studying KI GFAP mice (anatomopathology)
 Dr. MIGNOT Cyril: WP1: GFAP mutation database WP3 Pharmacological therapies in AXD using reliable cell culture and KI AXD mouse models;
 DUBIEF Emeline: WP2: Role of astrocytes in GFAP related disorders studying KI GFAP mice
24
(FRANCE)

Chouery, E., Delague, V., Jalkh, N., Salem, N., Kfoury, J., Rodriguez, D., Chabrol, B., Boespflug-Tanguy, O., Lévy, N., Serre, J.L., Mégarbané, A.
(2011) A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22. Neurogenetics. 2011 Feb;
12(1):73-8

Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G, Clément I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou
Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B. (2011) Mutations of POLR3A
encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011 Sep
9;89(3):415-23

Carra-Dalliere C, Horzinski L, Ayrignac X, Vukusic S, Rodriguez D, Mauguiere F, Peter L, Goizet C, Bouhour F, Denier C, Confavreux C, Obadia
M, Blanc F, de Seze J, Sedel F, Guennoc AM, Sartori E, Laplaud D, Antoine JC, Fogli A, Boespflug-Tanguy O, Labauge P. (2011) Natural history
of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases. Rev Neurol (Paris). 2011 Nov;167(11):802-11

Combes P, Planche V, Eymard-Pierre E, Sarret C, Rodriguez D, Boespflug-Tanguy O, Vaurs-Barriere C. (2012) Relevance of SOX17 Variants for
Hypomyelinating Leukodystrophies and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). 2012 May;76(3):261-67

Huyghe A, Horzinski L, Hénaut A, Gaillard M, Bertini E, Schiffmann R, Rodriguez D, Dantal Y, Boespflug-Tanguy O, Fogli A. (2012)

Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM,
Bacino CA, Battini R, Bertini E, Brogan PA, Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I, Fazzi E, Garcia-Cazorla
A, Heiberg A, Kawaguchi M, Kumar R, Lin JP, Lourenco CM, Male AM, Marques W Jr, Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen
M, Robinson RA, Rozenberg F, Schmidt JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling EL, Wassmer E,
Whittaker E, Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP, O'Connell MA, Lovell SC, Crow YJ. Mutations in ADAR1 cause
Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012 Nov;44(11):1243-8.
25
 THE UNIVERSITY OF MANCHESTER (UNITED KINGDOM)
THE RESEARCH UNIT
The Faculty of Life Sciences at the University of Manchester has over 1000 people involved in research, and an annual total budget of £65 million,
making it one of the largest and most successful unified research and teaching organisations of its kind in Europe. Over 300 FP6 programs were
awarded to UMAN and currently ~70 FP7 programs are ongoing.
Graham Pavitt, who directed the work at UMAN in Leukotreat, is an expert studying protein synthesis including the molecular structure-function of
eIF2B, the factor mutated in CACH/VWM disease. This work has included basic molecular biological and biochemical approaches to understand the
factor and the underlying biochemical consequences of mutations in eIF2B that result in CACH/VWM disease. He has also pioneered the
development of a yeast model system specifically to screen compounds for therapeutic activity towards eIF2B, which is defective in CACH/VWM
disease.
LeukoTreat Team: Dr. PAVITT Graham, Dr. CALLAN Hayley
ROLE IN THE PROJECT
 Pr. PAVITT Graham: WP2: Large scale production of eIF2; WP3: Development of yeast model system specifically to screen compounds for
therapeutic activity towards eIF2B which is defective in CACH/VWM disease
 Dr. DE ALMEIDA Rogerio: WP2: Large scale production of eIF2
 Dr. CALLAN Hayley: WP3: Setting up and performing compound screen and subsequent biochemical validation of hit compounds
 De Almeida, R., Fogli, A., Gaillard, M., Scheper, G.C., Boespflug-Tanguy, O., Pavitt, G.D. (2013) A Yeast Purification System for Human
Translation Initiation Factors eIF2 and eIF2BƐ and Their Use in the Diagnosis of CACH/VWM Disease. PLosOne. 2013 Jan 15; 8(1):e53958
26
 FUNDACIO INSTITUT D’INVESTIGACIO BIOMEDICA DE BELLVITGE
(SPAIN)
THE INSTITUTE
Bellvitge Biomedical Research Institute (IDIBELL) is a young research institution created in 2004, with more than 300 researchers. It is one of the
fastest-growing research institutions in Spain affiliated with the second largest hospital in Spain (Bellvitge Universitary Hospital-HUB). 10 research
projects have already been handled by IDIBELL during FP6. The scientific production of IDIBELL-HUB is the second largest of all clinical research
institutions in Spain. Dr Pujol started working in X-ALD 10 years ago, in the laboratory of JL Mandel, IGBMC, Strasbourg. Main contributions to the
field include the generation of mouse models for X-ALD, uncovering neurodegeneration in the X-ALD mouse and the role of oxidative stress in
disease etiopathogenesis.
LeukoTreat Team: Dr. PUJOL Aurora, GRAU Laia, Dr. FOURCADE Stéphane, ILIEVA Ekaterina, GUILERA Cristina, GALINO Jorge, LOPEZ-ERAUSKIN
Jone, MARTINEZ Juanjo
ROLE IN THE PROJECT
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Dr. PUJOL Aurora: WP2 leader, WP3 technical supervision
GRAU Laia: WP2: Support for redox proteomics and molecular biology studies in WP2 and WP3
Dr. FOURCADE Stéphane: WP2 technical supervision
ILIEVA Ekaterina, GALINO Jorge and LOPEZ-ERAUSKIN Jone: Redox proteomics studies and pharmacological therapies in preclinical settings
GUILERA Cristina and MARTINEZ Juanjo: Support for redox proteomics and mouse preclinical work
27
(SPAIN)

Fourcade S., Ruiz M., Guilera C., Hahnen E., Brichta L., Naudi A., Portero-Otín M., Dacremont G., Cartier N., Wanders R., Kemp S., Mandel
JM., Wirth B., Pamplona R., Aubourg P., Pujol A. (2010) Valproic acid induces antioxidant effects in X-ALD. Human Molecular Genetics 19(10):
2005-14

López-Erauskin, J., Fourcade, S., Galino, J., Ruiz, M., Schlüter, A., Naudi, A., Portero-Otin, M., Pamplona, R., Ferrer, I., Pujol, A. (2011)
Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann Neurol. 2011 Jul; 70(1):84-92

Galino J, Ruiz M, Fourcade S, Schlüter A, López-Erauskin J, Guilera C, Jove M, Naudi A, García-Arumí E, Andreu AL, Starkov AA, Pamplona R,
Ferrer I, Portero-Otin M, Pujol A. Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of Xadrenoleukodystrophy. Antioxid Redox Signal. 2011, Oct 15; 15(8):2095-107

Schlüter, A., Espinosa, L., Fourcade, S., Galino, J., Lopez, E., Ilieva, E., Morato, L., Asheuer, M., Cook, T., McLaren, A., Reid, J., Kelly, F., Bates,
S., Aubourg, P., Galea, E., Pujol, A. (2012) Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy.
Hum Mol. Genet. 2012 Mar 1; 21(5):1062-77

Engelen M, Schackmann MJA, Ofman R, Sanders RJ, Dijkstra IME, Houten SM, Fourcade S, Pujol A, Poll-The BT, Wanders RJ and Kemp S
(2012) Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation. J Inherit
Metab Dis. 35(6):1137-45

Galea E, Launay N, Portero-Otin M, Ruiz M, Pamplona R, Aubourg P, Ferrer I, Pujol A*. (2012) Oxidative stress underlying axonal
degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta. Sep
12;1822(9):1475-88

Lopez-Erauskin, J., Galino, J., Bianchi, P., Fourcade, S., Andreu, A.L., Ferrer, I., Muñoz-Pinedo, C., Pujol, A. (2012) Oxidative stress modulates
mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain. 2012 Dec; 135(12):3584-98

Launay N, Ruiz M, Fourcade S, Schlüter A, Guilera C, Ferrer I, Knecht E, Pujol A. Oxidative stress regulates the ubiquitin-proteasome system
and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy. Brain. 2013 Mar;136(Pt 3):891-904. doi:
10.1093/brain/aws370
28
(SPAIN)

Morató L., Galino J., Ruiz M., Calingasan N.Y., Starkov A.A., Dumont M., Naudí A., Martínez J.J., Aubourg P., Portero-Otín M., Pamplona R.,
adrenoleukodystrophy. Brain 2013 Jun 22; Epub ahead of print

Petrillo S., Piemonte F., Pastore A., Tozzi G., Aiello C., Pujol A., Cappa M., Bertini E. (2013) Glutathione imbalance in patients with X-linked
adrenoleukodystrophy. Mol Genet Metab. 2013 May 22;pii: S1096-7192(13)00175-3

López-Erauskin J., Galino J., Ruiz M., Cuezva J.M., Fabregat I., Cacabelos D., Boada J., Martínez J., Ferrer I., Pamplona R., Villarroya F.,
Portero-Otín M., Fourcade S., Pujol A. (2013) Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked
adrenoleukodystrophy. Hum Mol Genet. 22(16):3296-305

Fourcade S., López-Erauskin J., Ruiz M., Ferrer .I, Pujol A (2013). Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal
degeneration in X-linked adrenoleukodystrophy. Biochimie. 2013 Sep 24. pii: S0300-9084(13)00326-X

Morató L., Galino J., Ruiz M., Calingasan N.Y., Starkov A.A., Dumont M., Naudí A., Martínez J.J., Aubourg P., Portero-Otín M., Pamplona R.,
adrenoleukodystrophy. Brain. 2013 Aug;136(Pt 8):2432-43.

Fourcade S., López-Erauskin J., Ruiz M., Ferrer .I, Pujol A (2013). Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal
degeneration in X-linked adrenoleukodystrophy. Biochimie. 2014 Mar;98:143-9.
29
 MAX PLANCK GESELLSCHAFT ZUR FORDERUNG DES
WISSENSCHAFTEN E.V (GERMANY)
THE RESEARCH UNIT
The Max Planck Institute of Experimental Medicine is a research institute of the Max Planck Society that performs innovative, interdisciplinary
research in the neurosciences, with a major focus on translating basic research into preclinical and clinical research trials. The department directed
by Klaus-Armin NAVE studies neuron-glia interactions during normal development and in the pathological nervous system (neuropathies in the PNS
and leukodystrophies in the CNS) and has a proven record of successful preclinical therapy in rodent models. The department is part of the German
LeukoNet network. Pr. Nave participated in several EU grants (FP6: NeuroPromise, Peroxisomes, X-ALD, Cholesterol in vivo; FP7: Neuroglia, NGIDD).
LeukoTreat Team: Dr. WERNER Hauke, Dr. NAVE Klaus-Armin, Dr. SEREDA Michael
ROLE IN THE PROJECT
 Dr. WERNER Hauke: WP3 leader - WP3: Expert in myelin biology and pathology
 Dr. NAVE Klaus-Armin: WP3: Efficacy of Turmeric/Curcumin and progesterone-antagonist in PLPoverexpressor and PLPrumpshaker PMD-models
 Dr. SEREDA Michael: WP3: Efficacy of Turmeric/Curcumin and progesterone-antagonist
 Werner, H.B., Jahn, O. (2010) Myelin matters: Proteomic insights into white matter disorders. Expert Rev Proteomics. 2010 Apr; 7(2):159-64
 Nave, K.A. (2010) Myelination and the trophic support of long axons. Nat Rev Neurosci. 2010 Apr; 11(4): 275-83
 Kolodziejczyk, K., Saab, A.S., Nave, K.A., Attwell, D. (2010) Why do oligodendrocyte lineage cells express glutamate receptors? F1000 Biol. Rep.
2010 Aug 9; 2:57
 Nave, K.A. (2010) Myelination and support of axonal integrity by glia. Nature. 2010 Nov 11; 468(7321):244-52
 Dhaunchak, A.S., Colman, D.R., Nave, K.A. (2011) Misalignment of PLP/DM20 Transmembrane Domains Determines Protein Misfolding in
Pelizaeus-Merzbacher Disease. J Neurosci. 2011 Oct 19; 31(42):14961-71
30
 MAX PLANCK GESELLSCHAFT ZUR FORDERUNG DES
WISSENSCHAFTEN E.V (GERMANY)
 Patzig, J., Jahn, O., Tenzer, S., Wichert, S.P., de Monasterio-Schrader, P., Rosfa, S., Kuharev, J., Yan, K., Bormuth, I., Bremer,
J., Aguzzi, A., Orfaniotou, F., Hesse, D., Schwab, M.H., Möbius, W., Nave, K.A., Werner, H.B. (2011) Quantitative and Integrative
Proteome Analysis of Peripheral Nerve Myelin Identifies Novel Myelin Proteins and Candidate Neuropathy. Loci. J Neurosci. 2011
Nov 9; 31(45):16369-86.
 De Monasterio-Schrader P, Jahn O, Tenzer S, Wichert SP, Patzig J, Werner HB (2012). Systematic approches to central nervous system myelin.
Cell Mol Life Sci 69, 2879-94
 Goebbels S, Oltrogge JH, Wolfer S, Wieser GL, Nientiedt T, Pieper A, Ruhwedel T, Groszer M, Sereda MW, Nave KA (2012). Genetic disruption
of Pten in a novel mouse model of tomaculous neuropathy. EMBO Mol Med 4:486-99
 Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM, Tzvetanova ID, Möbius W, Diaz F, Meijer D,
Hamprecht B, Sereda MW, Moraes CT, Frahm J, Goebbels S, Nave KA (2012). Glycolytic oligodendrocytes maintain myelin and long-term axonal
integrity. Nature 485, 517-521
 Saher G, Rudolphi F, Corthals K, Ruhwedel T, Schmidt KF, Löwel S. Dibaj P, Barrette B, Möbius W, Nave KA (2012). Therapy of PelizaeusMerzbacher disease in mice by feeding a cholesterol-enriched diet. Nat Med 18, 1130-5
 Jahn O, Tenzer S, Bartsch N, Patzig J, Werner HB (2013) Myelin proteome analysis: methods and implications for the myelin cytoskeleton. In: The
Cytoskeleton: Imaging, Isolation, and Interaction. Neuromethods 79:335. Springer, ed: Dermietzel R.
 Werner HB, Krämer-Albers EM, Strenzke N, Saher G, Tenzer S, Ohno-Iwashita Y, De Monasterio-Schrader P, Möbius W, Moser T, Griffiths IR,
Nave KA (2013). A critical role for the cholesterol-associated proteolipids PLP and M6B in myelination of the central nervous system. Glia 61:56786
 Prukop T, Epplen DB, Nientiedt T, Wichert SP, Fledrich R, Stassart RM, Rossner MJ, Edgar JM, Werner HB, Nave KA, Sereda MW (2014)
Progesterone antagonist therapy in a Pelizaeus-Merzbacher mouse model. Am J Hum Genet 94:533-46
31
 MEDIZINISCHE UNIVERSITAET WIEN (AUSTRIA)
THE RESEARCH UNIT
For the past years, the research of MUW (MEDIZINISCHE UNIVERSITAET WIEN) has focused on the identification of the molecular mechanisms that
underlie X-ALD and the development of novel therapeutic strategies. Abcd1 knockout mice as a model for X-ALD have been generated, as well as
Abcd2 and Abcd1/Abcd2 double-deficient mice. MUW has contributed to mutation analyses in human X-ALD, the identification of the human ABCD2
gene, encoding the closest homologue of ALDP, and demonstrated that the ALDR protein can functionally compensate for the loss of ALDP in vitro.
Investigations are ongoing to identify candidate genes as possible modifiers in X-ALD. MUW has also contributed to a better understanding of the
genotype-phenotype correlation in MLD.
LeukoTreat Team: Pr. BERGER Johannes, Dr. FORSS-PETTER Sonja, HABERL Manuela, WIESINGER Christoph, EINWICH Angelika
ROLE IN THE PROJECT





Pr. BERGER Johannes: WP2: Genomic polymorphic markers for X-ALD prognostics; WP3: Pharmacological induction of ABCD2 in ALD
Dr. FORSS-PETTER Sonja: WP3: In charge of the animal experiments
HABERL Manuela: WP2: Mutation analysis; WP3: Genotyping of mice
WIESINGER Christoph: WP3: Improvement of ABCD1 and ABCD2 mRNA quantification and of the substate specificity of ABCD1
EINWICH Angelika : WP3: Evaluation of the efficacy of compounds to induce ABCD2 in monocytic cell lines

Barbier M, Sabbagh A, Kasper E, Asheuer M, Ahouansou O, Pribill I, Forss-Petter S, Vidaud M, Berger J, Aubourg P. (2012) CD1 gene
polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy. PLoS One. 7(1):e29872

Kemp S, Berger J, Aubourg P. (2012) X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects. BBA-Mol
Basis Dis. 1822(9):1465-74

Wiesinger C., Kunze M., Regelsberger G., Forss-Petter S., Berger J. (2013) Impaired Very Long-chain Acyl-CoA β-Oxidation in Human X-linked
Adrenoleukodystrophy Fibroblasts Is a Direct Consequence of ABCD1 Transporter Dysfunction. J Biol Chem. 288 (26): 19269-19279.
32
 MEDIZINISCHE UNIVERSITAET WIEN (AUSTRIA)

Weber F.D., Wiesinger C., Forss-Petter S., Regelsberger G., Einwich A., Weber W.H., Köhler W., Stockinger H., Berger J. (2014) X-linked
adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes. Hum Mol Genet. 23
(10): 2542-2550.

Weber F.D., Weinhofer I., Einwich A., Forss-Petter S., Munieer Z., Maier H., Weber W.H.A., Berger J. (2014) Evaluation of retinoids for
induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy. PLoS One. In press
33
 UNIVERSITY COLLEGE LONDON (UNITED KINGDOM)
THE RESEARCH UNIT
University College London is one of the 4 most important universities in the UK. Its expertise in neuroscience is particularly outstanding, as it
generates approximately 30% of England’s contribution to the world’s most highly cited papers in this field (more than twice as high as Oxford or
Cambridge). UCL has been involved, as partner and coordinator, in a large number of FP6 and FP7 projects.
LeukoTreat Team: Dr. ATTWELL David, Dr. BAKIRI Yamina, ARANCIBIA-CARCAMO Irma Lorena
ROLE IN THE PROJECT
 Dr. ATTWELL David: WP2: study of the effects of NAAG and NAA on oligodendrocytes and their precursors (patch-clamping and Ca imaging)
 Dr. BAKIRI Yamina: Patch-clamping and imaging oligodendrocyte precursor cells
 ARANCIBIA-CARCAMO Irma Lorena: Investigating myelination and demyelination in cultured brain slices
 Burzomato V., Frugier G., Pérez-Otaño I., Kittler J.T., Attwell, D. (2010) The receptor subunits generating NMDA receptor mediated currents in
oligodendrocytes. J. Physiol.; 588:3403-3413
 Kolodziejczyk, K., Saab, A.S., Nave, K.A., Attwell, D. (2010) Why do oligodendrocyte lineage cells express glutamate receptors? F1000 Biol. Rep.
2010 Aug 9; 2:57
 Rinholm, J.E., Hamilton, N.B., Kessaris, N., Richardson, W.D., Bergersen, L.H. & Attwell, D. (2011) Regulation of oligodendrocyte development
and myelination by glucose and lactate. J. Neurosci. 2011 Jan 12; 31(2):538-48
 Bakiri, Y., Karadottir, R., Cossell, L., Attwell, D. (2011) Morphological and electrical properties of oligodendrocytes in the white matter of the
corpus callosum and cerebellum. J. Physiol. 2011 Feb 1; 589:559-73
 Clarke, L.E., Young, K.M., Hamilton, N.B., Li, H., Richardson, W.D. & Attwell D. (2012) Properties and fate of oligodendrocyte progenitor cells in
the corpus callosum, motor cortex, and piriform cortex of the mouse. J. Neurosci. 32, 8173-8185
 Harris J.J., Attwell D. (2013) Is myelin a mitochondrion? J. Cereb. Blood Flow Metab. 2013 Jan;33(1):33-6 34
 FONDAZIONE CENTRO SAN RAFAELLE DEL MONTE TABOR (ITALY)
THE RESEARCH UNIT
The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) was created in 1995 as a joint-venture between the San Raffaele Scientific
Institute and the Telethon Foundation. The mission of the Institute is to perform cutting edge science in the field of gene therapy and to promote
the translation of basic discoveries into therapeutic advances. The genetic diseases that are presently under investigation (from those in advanced
clinical experimentation to those in early pre-clinical development) include primary immunodeficiencies, lysosomal storage disorders including
leukodystrophies, type I diabetes, hemophilias, thalassemias. HSR-TIGET is a partner within CONSERT, a FP6 project on gene therapy development,
and the Director of HSR-TIGET is coordinating a newly approved FP7 project (PERSIST).
LeukoTreat Team: Dr. BIFFI Alessandra, Dr. GRITTI Angela, Dr. SESSA Maria
ROLE IN THE PROJECT



Dr. BIFFI Alessandra: gene therapy approaches based on hematopoietic stem cells and lentiviral vectors for the treatment of leukodystrophies
Dr. GRITTI Angela: gene/neural stem cell therapies and lentiviral-mediated CNS gene delivery for leukodystrophies will coordinate
Dr. SESSA Maria: WP1: Participation to the clinical database and biobank with expertise for MLD

Visigalli I, Ungari S, Martino S, Park H, Cesani M, Gentner B, Sergi L, Orlacchio A, Naldini L, Biffi A. (2010) The galactocerebrosidase enzyme
contributes to the maintenance of a functional hematopoietic stem cell niche. Blood. 2010 Sep;116(11):1857-66

Gentner, B., Visigalli, I., Hiramatsu, H., Lechman, E., Ungari, S., Giustacchini, A., Schira, G., Amendola, M., Quattrini, A., Martino, S.,
Orlacchio, A., Dick, J.E., Biffi, A., Naldini, L. (2010) Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid
cell leukodystrophy. Sci Transl Med. 2010 Nov 17; 2(58):58ra84

Lattanzi A, Neri M, Maderna C, di Girolamo I, Martino S, Orlacchio A, Amendola M, Naldini L, Gritti A. Widespread enzymatic correction of
CNS tissues by a single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models. Hum Mol Genet. 2010 Jun
1;19(11):2208-27

Biffi A, Aubourg P, Cartier N. (2011) Gene therapy for leukodystrophies. Hum Mol Genet. 2011 Apr;20(R1):R42-R53
35
 FONDAZIONE CENTRO SAN RAFAELLE DEL MONTE TABOR (ITALY)

Visigalli I, Biffi A. (2011) Maintenance of a functional hematopoietic stem cell niche through galactocerebrosidase and other
enzymes. Current Opinion in Hematology. 2011 Jul;18(4):214-19

Neri M, Ricca A, di Girolamo I, Alcala-Franco B, Cavazzin C, Orlacchio A, Martino S, Naldini L, Gritti A. (2011) Neural Stem Cell Gene Therapy
Ameliorates Pathology and Function in a Mouse Model of Globoid Cell Leukodystrophy. Stem Cells. 2011 Oct; 29(10):1559-1571

Gritti A. Gene therapy for lysosomal storage disorders. Expert Opin Biol Ther. Sep;11(9):1153-67 2011 Epub 2011 May 9

Capotondo A., Milazzo R., Politi L.S., Quattrini A., Palini A., Plati T., Merella S., Nonis A., di Serio C., Montini E., Naldini L., Biffi A. (2012)
Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cells transplantation. Proc Natl Acad
Sci U S A. 2012 Sep 11;109(37):15018-23

Santambrogio S, Ricca A, Maderna C, Ieraci A, Aureli A, Sonnino S, Kulik W, Aimar P, Bonfanti L, Martino S and Gritti A. The
galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development Human
Molecular Genetics 2012; Nov 1;21(21):4732-50 doi: 10.1093/hmg/dds313

Biffi A., Montini E., Lorioli L., Cesani M., Fumagalli F., Plati T., Martino S., Baldoli C., Calabria A., Canale S., Benedicenti F., Vallanti G., Biasco
L., Leo S., Kabbara N., Zanetti G., Rizzo W.B., Metha N.AL., Cicalese M.P., Casiraghi M., Boelens J.J., del Carro U., Dow D.J., Schimdt M., di
Serio C., Stupka E., von Kalle C., Bordignon C., Ciceri F., Rovelli A., Roncarolo M.G., Aiuti A., Sessa M., Naldini L. (2013) Extensive Genetic
Engineering of Hematopoiesis with Therapeutic Benefit in Metachromatic Leukodystrophy Patients after Lentiviral hematopoietic stem cells
Gene Therapy. Science; 341(6148):1233158
36
 ACADEMISCH MEDISCH CENTRUM (THE NETHERLANDS)
THE RESEARCH UNIT
The Laboratory of Genetic Metabolic Diseases of AMC (ACADEMISCH MEDISCH CENTRUM) is a joint Diagnostic and Research laboratory, has strong
bonds with different clinical disciplines, notably Pediatrics, (Child)Neurology, Clinical Genetics, and Internal Medicine, and belongs to the
Amsterdam Center of Metabolism, one of the spearheads within the Medical Faculty of the University of Amsterdam, at the Amsterdam Medical
Center. The laboratory covers the full spectrum of techniques, ranging from metabolite to enzyme and DNA analysis as required for identification of
patients suspected to suffer from an inborn error of metabolism. Next to these diagnostic activities the laboratory has a number of research lines of
which research on Peroxisomal Diseases is one of the strongest.
LeukoTreat Team: Pr. WANDERS Ronald, Dr. KEMP Stephan, Dr. KULIK Wim, SCHACKMANN Martin
ROLE IN THE PROJECT



Pr. WANDERS Ronald: Overall supervision, expertise on Enzymology, Lipid Metabolism, and Cell Biology
Dr. KEMP Stephan with SCHACKMANN Martin: WP3: small compound screening to rescue misfolded ALD protein
Dr. KULIK Wim: WP2: metabolite analyses, including lipodomics, using (UPLC-) tandem-MS
37
 ACADEMISCH MEDISCH CENTRUM (THE NETHERLANDS)

Fourcade, S., Ruiz, M., Guilera, C., Hahnen, E., Brichta, L., Naudi, A., Portero-Otín, M., Dacremont,G., Cartier, N., Wanders, R., Kemp, S.,
Mandel, J.M., Wirth, B., Pamplona, R., Aubourg, P., Pujol, A. (2010) Valproic acid induces antioxidant effects in X-ALD. Hum Mol Genet. 2010
May 15; 19(10): 2005-14

Zhang X., De Marcos Lousa C., Schutte-Lensink N., Ofman R., Wanders R.J., Baldwin S.A., Baker A,. Kemp S., Theodoulou F.L. (2011)
Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom
expression. Biochem J. 2011 Jun 15; 436(3):547-57

Sarret, C., Rigal, M., Vaurs-Barrière, C., Dorbiz, I., Eymard-Pierre, E., Combes, P., Giraud, G., Wanders, R.J., Afenjar, A., Francannet, C.,
312(1-2):123-6

Engelen, M., Tran, L., Ofman, R., Brennecke, J., Moser, A.B., Dijkstra, I.M., Wanders, R.J., Poll-The, B.T., Kemp, S. (2012) Bezafibrate for xlinked adrenoleukodystrophy. PLoS One. 2012 Jul;7(7):e41013

Kemp, S., Berger, J., Aubourg, P. (2012) X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim
Biophys Acta. 2012 Sep;1822(9):1465-74

Engelen, M., Schackmann, M.J., Ofman, R., Sanders, R.J., Dijkstra, I.M., Houten, S.M., Fourcade, S., Pujol, A., Poll-The, B.T., Wanders, R.J.,
Kemp, S. (2012) Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation.
J Inherit Metab Dis. 2012 Nov; 35(6):1137-45

Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJA, Aubourg PA, Poll-The BT (2012) X-linked adrenoleukodystrophy (X-ALD): clinical
presentation and guidelines for diagnosis, follow-up and management. Orphanet Journal of Rare Diseases. 7(1):51

Aubourg P., Wanders R. (2013) Peroxisomal disorders. Handb Clin Neurol. 2013;113:1593-609
38
 UNIVERSITE PARIS DESCARTES (FRANCE)
THE RESEARCH UNIT
The Laboratory of Medical Ethics (LEM) at the Faculty of Medicine of Paris Descartes University has been developing ethical research on the analysis
of practices and patients’ life experience for the last 15 years. Its expertise relies on patients’ rights, integration of patients’ needs in the health care
system, and the protection of persons in health care and biomedical research.
LeukoTreat Team: Dr. MOUTEL Grégoire, Dr. DUCHANGE Nathalie, Dr. CALLIES Ingrid, Dr. DARQUY Sylviane, LECLERCQ Thomas, LOEVE Boris,
LAPOINTE Anne-Sophie, d’AUDIFFRET Diane
ROLE IN THE PROJECT


Dr. MOUTEL Grégoire: WP5 leader. Coordination of the ethical issues raised by data and samples collections, accessibility of patients to the
research, innovative therapies
Dr. DUCHANGE Nathalie: Co coordination of the WP5
WP5: Study of patients/families view about the LeukoDataBase
WP6 : Dissemination
WP7 : Ethical management
Duchange N, Darquy S, d’Audiffret D, Callies I, Lapointe A-S, Loeve B, Boespflug-Tanguy O. Moutel G. Ethical management in the constitution
of a European database for leukodystrophies rare diseases. Eur J Paediatr Neurol. 2014 Apr 14. pii: S1090-3798(14)00054-3. doi:
10.1016/j.ejpn.2014.04.002
39
 THE UNIVERSITY OF CAMBRIDGE (UNITED KINDGOM)
THE RESEARCH UNIT
The Vet School at the University of Cambridge (CMSUC) is a leading centre in the UK for the study of white matter diseases of the brain. The
Karadottir laboratory provides an environment for the work in which patch-clamping is combined with confocal microscopy, and the surrounding
groups of Robin Franklin and others offer helpful intellectual input to the work.
LeukoTreat Team: Dr. Ragnhildur Thora KARADOTTIR, John Stockley
ROLE IN THE PROJECT


Dr. Ragnhildur Thora KARADOTTIR: WP2: Using the patch-clamp and immunocytochemical experience, CMSUC studied the effect of NAAG and
NAA on oligodendrocyte precursor cells
John Stockley: WP2: used immunocytochemical and molecular experience to study the effect of NAAG and NAA on oligodendrocyte precursor
cells and myelin
 Bakiri, Y., Karadottir, R., Cossell, L., Attwell, D. (2011) Morphological and electrical properties of oligodendrocytes in the white matter of the
corpus callosum and cerebellum. J. Physiol. 2011 Feb 1; 589:559-73
 Káradóttir R, Stockley JH (2012) Deconstructing myelination: it all comes down to size. Nature Methods 9(9):883-4
 Lundgaard I, Luzhynskaya A, Stockley J.H, Wang Z, Evans KA, Swire M, Volbracht K, Gautier H.O., Franklin RJM., ffrench-Constant C, Attwell D
& Káradóttir R (2013). Neuregulin and BDNF induce a switch to NMDA receptor dependent myelination by oligodendrocytes. PLoS Biol
11(12):e1001743
40
 UNIVERSITE PARIS DIDEROT – PARIS 7 (FRANCE)
THE RESEARCH UNIT
Pr. Odile Boespflug-Tanguy has moved to a new institution, Université Paris Diderot – Paris 7. As previously stated, her team aims at studying glial
cell interactions during normal and pathological development of CNS.
LeukoTreat Team: Pr. BOESPFLUG-TANGUY Odile, Dr. RENALDO Florence, Dr. DORBOZ Imen
ROLE IN THE PROJECT
 Pr. BOESPFLUG-TANGUY Odile: Coordinator of the LeukoTreat project
WP1: Supervision of the clinical /molecular expertise of patients provided by the LeukoFrance network
WP2: Supervision of the NAA/NAAG analysis in LD patients
WP3: Supervision of the mitochondrial targeted cholesterol derivatives in mice Plp1 mutants
WP4: Development of gene silencing approaches to treat LDs
WP5: Supervision of family/patients recruitments in institutions
•
•
•
•
•
Florence Renaldo (WP1)
Davide Ronduti (WP1)
Samia Pichard (WP1)
Imen Dorboz (WP1)
Marie Louise Vendeville (WP5)
41

Chouery, E., Delague, V., Jalkh, N., Salem, N., Kfoury, J., Rodriguez, D., Chabrol, B., Boespflug-Tanguy, O., Lévy, N., Serre, J.L., Mégarbané, A.
(2011) A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22. Neurogenetics. 2011 Feb;
12(1):73-8

Labauge, P., Dorboz, I., Eymard-Pierre, E., Dereeper, O., Boespflug-Tanguy, O. (2011) Clinically asymptomatic adult patient with extensive
LBSL MRI pattern and DARS2 mutations. J Neurol. 2011 Feb; 258(2):335-37

Boespflug-Tanguy, O., Aubourg, P., Dorboz, I., Bégou, M., Giraud, G., Sarret, C., Vaurs-Barrière, C. (2011) Neurodegenerative disorder related
to AIMP1/p43 mutation is not a PMLD. Am J Hum Genet. 2011 Mar 11; 88(3):392-93; author reply 393-95

Grossi S, Regis S, Biancheri R, Mort M, Lualdi S, Bertini E, Uziel G, Boespflug-Tanguy O, Simonati A, Corsolini F, Demir E, Marchiani V,
Percesepe A, Stanzial F, Rossi A, Vaurs-Barrière C, Cooper DN, Filocamo M. Molecular genetic analysis of the PLP1 gene in 38 families with
PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis. 2011 Jun 16;6:40.

Bernard, G., Chouery, E., Putorti, M.L., Tétreault, M., Takanohashi, A., Carosso, G., Clément, I., Boespflug-Tanguy, O., Rodriguez, D., Delague
V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. (2011)
Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum
Genet. 2011 Sep 9; 89(3):415-23

Carra-Dalliere, C., Horzinski, L., Ayrignac, X., Vukusic, S., Rodriguez, D., Mauguiere, F., Peter, L., Goizet, C., Bouhour, F., Denier, C.,
Confavreux, C., Obadia, M., Blanc, F., de Seze, J., Guennoc, A.M., Sartori, E., Laplaud, D., Antoine, J.C., Fogli, A., Boespflug-Tanguy, O.,
Labauge, P. (2011) Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases. Rev Neurol (Paris). 2011 Nov;
167(11):802-11

Sarret, C., Rigal, M., Vaurs-Barrière, C., Dorbiz, I., Eymard-Pierre, E., Combes, P., Giraud, G., Wanders, R.J., Afenjar, A., Francannet, C.,
312(1-2):123-6

Combes, P., Kammoun, N., Monnier, A., Gonthier-Guéret, C., Giraud, G., Bertini, E., Chahnez, T., Fakhfakh, F., Boespflug-Tanguy, O, VaursBarrière, C. (2012) Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. Ann Neurol. 2012 Jan; 71(1):146-48
42

Combes, P., Planche, V., Eymard-Pierre, E., Sarret, C., Rodriguez, D., Boesplug-Tanguy, O., Vaurs-Barrière, C. (2012) Relevance of SOX17
Variants for Hypomyelinating Leukodystrophies and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Ann Hum Genet. 2012
May; 76(3):261-267

Huyghe, A., Horzinski, L., Hénaut, A., Gaillard, M., Bertini, E., Schiffmann, R., Rodriguez, D., Dantal, Y., Boespflug-Tanguy, O., Fogli, A. (2012)
Developmental Splicing Deregulation in Leukodystrophies related to EIF2B Mutations. PLoS One. 2012 Jun; 7(6):e38264

Fogli, A., Merle, C., Roussel, V., Schiffmann, R., Ughetto, S., Theisen, M., Boespflug-Tanguy, O. (2012) CSF N-Glycan Profiles to Investigate
Biomarkers in Brain Developmental Disorders: Application to Leukodystrophies Related to eIF2B Mutations. PLoS One. 2012 Aug;7(8):e42688

De Almeida, R., Fogli, A., Gaillard, M., Scheper, G.C., Boespflug-Tanguy, O., Pavitt, G.D. (2013) A Yeast Purification System for
Human Translation Initiation Factors eIF2 and eIF2BƐ and Their Use in the Diagnosis of CACH/VWM Disease. PLosOne. 2013 Jan 15;
8(1):e53958
43

FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
(ITALY)
THE RESEARCH UNIT
The Istituto Neurologico in Milan is the major public health institution devoted to clinical neuroscience in Italy. The National Neurological Institute
(NNI) has a longstanding tradition in the study of genetic neurodegenerative disorders, particularly in disorders of the white matter. This is the result
of a fruitful collaborations among different clinical units including child neurology, neurology, neuroradiology, neurophysiology, and laboratories of
research and diagnosis. A large number of patients with leukoencephalopathies and leukodystrophies are followed at the NNI.
LeukoTreat Team: Dr. UZIEL Graziella, Dr. GENETRINI Silvia
ROLE IN THE PROJECT


Dr. UZIEL Graziella: WP1: Clinical data collection and biobank management
Dr. GENETRINI Silvia: WP1: Clinical data collection and biobank management

Grossi S, Regis S, Biancheri R, Mort M, Lualdi S, Bertini E, Uziel G, Boespflug-Tanguy O, Simonati A, Corsolini F, Demir E, Marchiani V,
Percesepe A, Stanzial F, Rossi A, Vaurs-Barrière C, Cooper DN, Filocamo M. Molecular genetic analysis of the PLP1 gene in 38 families with
PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis. 2011 Jun 16;6:40

Salsano, E., Tabano, S., Sirchia, S.M., Colapietro, P., Castellotti, B., Gellera, C., Rimoldi, M., Pensato, V., Mariotti, C., Pareyson, D., Miozzo,
M., Uziel, G. (2012) Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to
clinical symptoms. Orphanet J Rare Dis. 2012 Jan 26; 7:10

Livingstone, J., Graziano, C., Pysden, K., Crow, Y., Mordekar, S.J., Moroni, I., Uziel, G. (2012) Intracranial calcification in early infantile Krabbe
disease: nothing new under the sun. Developmental Medicine & Child Neurology. 2012 Apr; 54(4):376-79

Salsano, E., Gambini, O., Giovagnoli, A.R., Farina, L., Uziel, G., Pareyson, D. (2012) Effectiveness of valproate for the treatment of manic-like
behavior in X-linked adrenoleukodystrophy. Neurol Sci. 2012 Oct; 33(5):1197-99
44
 UNIVERSITAETSKLINIKUM HAMBURG – EPPENDORF
(GERMANY)
THE RESEARCH UNIT
The Department of Paediatrics of the University Medical Centre Hamburg-Eppendorf is a clinical centre with longstanding expertise in diagnosis and
management of leukodystrophies. It is one of the clinical reference centres for leukodystrophies within the Geman Leukodystrophy Network
(Leukonet).
LeukoTreat Team: Pr. KOHLSCHÜTTER Alfried, Dr. BLEY Annette
ROLE IN THE PROJECT
WP1: Clinical Data Management for Germany regarding all leukodystrophy forms with the exception of metachromatic leukodystrophy and Krabbe
disease
 Kohlschütter, A., Eichler, F. (2011) Childhood leukodystrophies: a clinical perspective. Expert Review of Neurotherapeutics. 2011 Oct;
11(10):1485-96
 Kohlschutter A (2011) Evaluating experimental treatment of leukodystrophies. Dev Med Child Neurol 53(9): 781
 Groeschel S., Kehrer C., Engel C., Dali C., Bley A., Steinfeld R., Grodd W., Krägeloh-Mann I. (2011) Metachromatic leukodystrophy: Natural
course of cerebral MRI changes in relation to clinical course. J Inherit Metab Dis. 2011 Oct; 34(5):1095-1102
45
 EBERHARD KARLS UNIVERSITAET TUEBINGEN
(GERMANY)
THE RESEARCH UNIT
The Tübingen department of Paediatric and Developmental Neurology has a special interest in early brain lesions, their epidemiology, and
characterisation on a functional and morphological level including advanced imaging and standardized measures for motor and cognitive functions.
A second field of interest is the clinical and biochemical characterization of sphingolipidoses, especially Metachromatic Leukodystrophy and Krabbe
Disease. Since 40 years a laboratory for enzyme measurements in sphingolipidoses is running. As described above, in the framework of the German
Leukonet, nation wide leukodystrophy registry and disease specific data banks for selected leukodystrophies have been established and physically
located at the Neuropediatrics Department at the University of Tübingen.
LeukoTreat Team: Pr. KRÄGELOH-MANN Ingeborg, BRAUN Silke, GRÖSCHEL Samuel, KEHRER Christiane
ROLE IN THE PROJECT
• WP1: management of the German clinical data for metachromatic leukodystrophy and Krabbe disease. Management of all biological data for
Germany
46
(GERMANY)

Kehrer, C., Blumenstock, G., Raabe, C., Krägeloh-Mann, I. (2011) Development and reliability of a classification system for gross motor function
in children with metachromatic leukodystrophy. Dev Med Child Neurol. 2011 Feb; 53(2):156-60

Kehrer, C., Blumenstock, G., Gieselmann, V., Krägeloh-Mann, I, on behalf of the German Leukonet.(2011) The natural course of gross motor
deterioration in metachromatic leukodystrophy. Dev Med Child Neurol. 2011 Sep; 53(9):850-5

Groeschel, S., Kehrer, C., Engel, C., I Dali, C., Bley, A., Steinfeld R., Grodd, W., Krägeloh-Mann, I. (2011) Metachromatic leukodystrophy:
Natural course of cerebral MRI changes in relation to clinical course. J Inherit Metab Dis. 2011 Oct; 34(5):1095-1102

Gieselmann V, Krägeloh-Mann I. Metachromatic Leukodystrophy. In: Raymond G, Eichler F Fatemi A, Naidu S (Ed.) “Leukodystrophies”, Mac
Keith Press, London, 2011, p. 130-155

Clas, P., Groeschel, S. (2011) Wie kann man eine Leukodystrophie messen? Journal des Bundesvereins Leukodystrophie. December 2011

Clas, P., Groeschel, S., Wilke, M. (2012) A semi-automatic algorithm for determining the demyelination load in metachromatic leukodystrophy.
Acad. Radiol. 2012 Jan; 19(1):26-34

Krägeloh-Mann I; Groeschel S; Kehrer C; Opherk K; Nägele T; Handgretinger R; Müller I. Juvenlie metachromatic leukodystrophy 10 years post
transplant compared with a non-transplanted cohort. Bone Marrow Transplant. 2012 Sep 3. doi: 10.1038/bmt.2012.155

Groeschel S; I Dali C; Clas P; Böhringer J; Duno M; Krarup C; Kehrer C; Wilke M; Krägeloh-Mann I. Cerebral gray and white matter changes and
clinical course in metachromatic leukodystrophy. Neurology. 2012 Oct 16; 79(16):1662-70. doi: 10.1212/WNL.0b013e31826e9ad2. Epub 2012
Sep 19

Krägeloh-Mann I; Kehrer C; Gieselmann V. Metachromatic leukodystrophy – what is new? Padiatr Croat 2012; 56:115-118
47
(GERMANY)

Gieselmann V, Wenger D, Krägeloh-Mann I. Metachromatic Leukodystrophy and Globoid Cell Leukodystrophy. In: Mehta A, Winchester B (Ed.),
Lysosomal Storage Disorders. John Wiley & Sons, 2012, p. 70-79

Kehrer C; Gröschel S; Kustermann-Kuhn B; Bürger F; Köhler W; Kohlschütter A; Bley A; Steinfeld R; Gieselmann V; Krägeloh-Mann I. Language
and cognition in children with metachromatic leukodystrophy: onset and natural course in a nationwide cohort. Orphanet Journal of Rare
Diseases 2014, 9:18, 1-9
48
 UNIVERSITY OF NEW SOUTH WALES (AUSTRALIA)
THE LABORATORY
The UNSW Faculty of Medecine takes a strategic view of Research and aims to focus its resources on Brain Sciences as an identified area of research
excellence. Dr Klugmann’s lab is situated within the Department of Physiology, and is part of the newly established Translational Neuroscience
Facility (TNF), new research development in the School of Medical Sciences. Several collaborating teams are embedded within the facility and their
research focus spans from sensory and motor systems to pathophysiology of neurological disorders. A state-of-the-art PC2 environment provides all
equipment for molecular biology, biochemistry and histology. An animal facility is in place hosting both animal housing and behavioural testing
facilities. A PC2 small animals surgery is available. M. Klugmann is director of the AAV vector core where the latest vector innovations will be
manufactured.
LeukoTreat Team: Dr. KLUGMANN Matthias, KLUGMANN Claudia, TEAHAN Oria, JONQUIERES Georg
ROLE IN THE PROJECT




Dr. KLUGMANN Matthias: WP4: Expert at the techniques to be used to study the efficacy of novel AAV vectors with potential to target
oligodendrocytes
KLUGMANN Claudia: Production of AAV vectors
TEAHAN Oria: NMR measurements of NAA and other brain metabolites
JONQUIERES Georg: Design and production of AAV variants, characterization of vector tropism, gene therapy in the mouse model, creation of
conditional ASPA mutants
• von Jonquieres, G., Mersmann, N., Klugmann, C.B., Harasta, A.E., Lutz, B., Teahan, O., Housley, G.D., Fröhlich, D., Krämer-Albers, E.-M.,
Klugmann, M. (2013). Glial promoter selectivity following AAV-delivery to the immature brain. PLoS ONE. 8(6): e65646
49
 TROPHOS SA (FRANCE)
THE COMPANY
TROPHOS is a clinical stage biopharmaceutical company committed to the discovery and development of innovative therapeutics for neurological,
cardiac and hepatic diseases. It was founded in 1999 by a group of entrepreneurs and academic scientists as a spin off of the laboratory of Professor
Christopher Henderson, a world expert in motor neuron biology and diseases. The Trophos drug discovery strategy involves the phenotypic
screening of small molecules to identify those that confer a survival benefit in models of primary neurons subjected to a pathophysiologically
relevant stress. Trophos has identified a new class of compounds targeting mitochondrial dysfunction that confers a survival benefit under stressed
conditions. Trophos has considerable experience in drug discovery and development for neurological indications and in particular for orphan
diseases such as SMA, ALS (amyotrophic lateral sclerosis) and HD (Huntington’s Disease).
LeukoTreat Team: Dr. BORDET Thierry, Dr. MICHAUD Magali, CHAIMBAULT Corinne, AFXANTIDIS Jean, LONSKI Priska, HOCINE Mélanie
ROLE IN THE PROJECT





Dr. BORDET Thierry with Dr. MICHAUD Magali: WP3: Coordination of the Trophos’ actions with other LeukoTreat partners. Direct the work to
select the compound to be evaluated in the LeukoTreat project. Provide drug compound as food pellets, and to perform pharmacokinetic and
toxicology studies
CHAIMBAULT Corinne: Direct the work to synthesize drug compound
AFXANTIDIS Jean: Direct the work to develop suitable analytical methods, to perform stability studies on drug formulation and to perform
bioanalysis in plasma and tissues samples
LONSKI Priska: Performance of analytical studies
HOCINE Mélanie: Performance of pharmacokinetic and toxicology studies
50
 SOLUSCIENCE SA (FRANCE)
THE COMPANY
Soluscience is a young company founded by two PhD graduates from the Ecole Polytechnique, France. Soluscience is a team of computer specialists,
scientists and documentation specialists that develops computer tools to solve various problems (increasing size and complexity of scientific
software; spectacular growth of valorization projects; multiplicity of the disciplines and competencies). Soluscience develops the information system
LeukoFrance with Professor Odile Boespflug-Tanguy.
LeukoTreat Team: Dr. DANTAL Yann , Dr. HAUG Christophe, Dr. DUPLANT Sébastien, LUQUET Sébastien
ROLE IN THE PROJECT
 WP1: Core system resulting from the connection of the existing national reference centers in France, Germany and Italy to collect data at the
European level
 WP5: Core system for ethical research including families access
 Huyghe A, Horzinski L, Hénaut A, Gaillard M, Bertini E, Schiffmann R, Rodriguez D, Dantal Y, Boespflug-Tanguy O, Fogli A. (2012)
51
 FRANCE EUROPE INNOVATION (FRANCE)
THE COMPANY
France Europe Innovation (FEI) is a French company represented by Olivier Degrand who proposes assistance and training for all kinds of
organizations (Universities, SME, RTD performers…) wanting to take part in European projects partly funded by the European Commission, as
coordinator or as partners. FEI (www.france-europe-innovation.fr) notably intervenes close to them in the administrative and financial coordination of their projects.
LeukoTreat Team: DEGRAND Olivier, CHATARD Delphine, Soline Le Villio
ROLE IN THE PROJECT


WP6: Dissemination
WP7: Administrative and financial co-coordination
52
 EUROPEAN ASSOCIATION AGAINST LEUKODYSTROPHIES – ELA
THE ASSOCIATION
Founded in 1992, the European Association against Leukodystrophies (ELA) is an association of parents and patients. Its objectives are to assist and
support families affected by leukodystrophy, stimulate the development of research through the ELA foundation established in 2005 and raise
public awareness. ELA is a hyphen between all leukodystrophies and a network of solidarity for families. It is also part of an international network of
information and research on the disease through its regular and constructive relations with its counterparts around the world.
LeukoTreat Team: ALBA Guy, FAVEAUX Philippe, DURAN Marie-Josée
ROLE IN THE PROJECT
 WP1, WP5 and WP6: Responsible for making the link with European patients, their families and other European associations
53
DISSEMINATION & INTEGRATION
PUBLICATIONS & PARTICIPATION TO EVENTS
The LeukoTreat partners have published more than 70 scientific publications related to the Project and participated
to many events: the annual ELA Families / Scientists Meeting, the International Society for Neuroimmunology
Meeting, the Gene Therapy Symposium, the European Pediatric Neurology Society Meeting, to name only a few.
For more information and to see the full list of publications and participation to events, please visit our dedicated
page on www.leukotreat.eu/publications-communications-news.
JOIN THE PATIENT DATABASE (LeukoDataBase)
One of LeukoTreat main objective was to collect a maximum of LDs data thanks to the LeukoTreat data base (see
result 1). Any LD patient and his/her family can participate directly to the advancement of this database by
entering themselves their data in the LeukoTreat Database. More information to come on www.leukotreat.eu.
54
PERSPECTIVES

What next for the LeukoDataBase ?
The ELA foundation (www.ela-asso.com) will be in charge of managing and developing the LeukoDataBase asof the end
of the project.
The LeukoDataBase will be used first of all as a European register of patients. It will not only facilitate recruitment of
patients but, knowing the high number of a specific form of leukodystrophy, it will have implications on the design and
power of a given therapeutic clinical trial.
The clinical database will facilitate epidemiological data about the overall number of this group of rare disorders. It will
also allow to know more about the distribution of each specific form of leukodystrophy in Europe. The Biological Sample
database will offer a repository of biological samples to all the research community in order to accelerate and facilitate
functional studies on the different forms of leukodystrophies. Finally, the Mutation Data for each gene known to be
implicated in leukodystrophies will give the possibility to integrate the clinical epidemiological data and define the hot
spot mutations for each form of leukodystrophy so that it will be easier to implement the diagnostic molecular genetic
procedures for this group of rare disorders.
The LeukoDataBase is part of a European effort to set up a transnational database for rare diseases (for more
information, please visit the FP7 RD-Connect project website: www.rd-connect.eu).
 Biomarkers
Biomarkers can be useful to pinpoint derangement in molecular pathways of potential value for understanding disease
pathogenesis, and can be as well useful for monitoring disease progression or drug effects. Using redox proteomics, we
have identified oxidation to proteins as a common marker to X-ALD, MLD, PMD. This has been validated as a marker for
X-ALD patients, useful to monitor antioxidant treatments. Lipidomics holds promise in the identification of novel lipidic
markers for the leukodystrophies, both for better understanding the disease state, and for monitoring treatment effects.
Challenges ahead include the integration of results of several –omic approaches, which will provide the most robust
outcomes in terms of disease target identification and relevance for disease understanding.
55

Challenges ahead for pharmacological therapies
Funding of the LeukoTreat consortium by the European Community has allowed major progress with respect to current
therapeutic concepts for various leukodystrophies, in particular for X-ALD, PMD, and MLD. This includes the systematic
screening for molecules with neuroprotective or anti-oxidant/anti-inflammatory activity, molecules that clear
misfolded proteins or that enhance protein-translation, and the application to in vitro and in vivo models of prototypic
leukodystrophies.
Some molecules are under final evaluation for the initiation of preclinical/clinical therapy trials. Importantly, the
molecular and cellular pathobiology of all leukodystrophies differs in principle. This prevents therapeutic concepts
designed for one particular leukodystrophy from being directly applied to a different leukodystrophy. This makes it very
valuable that the therapeutic efficacy of antioxidant dietary supplements has now been demonstrated in models of XALD and PMD. A related proof-of-concept clinical trial for X-ALD has been initiated, and a human clinical trial for X-ALD
has been approved. A proof-of-concept clinical trial for PMD will require an additional prior preclinical trial to test the
efficacy of a modified active substance with improved bioavailability. The blood-brain barrier is the major obstacle for
enzyme replacement therapy in MLD.
Preclinical and clinical trials are needed to evaluate the benefit of direct enzyme delivery to the cerebrospinal fluid and
the therapeutic potential of less invasive strategies using therapeutic enzyme modified to overcome the blood-brain
barrier. While LeukoTreat has emphasized the progression of therapy concepts, it also became evident that further
understanding of white matter physiology and pathophysiology will be required to develop rational therapy concepts for
the majority of other leukodystrophies. Finally, LeukoTreat has fostered the direct cooperation between basic researchers
and clinicians, which will be crucial for the success of the consortium’s common aims also after the end of project.
56

Challenges ahead for Gene & Cell Therapies
The proof-of-concept (POC) in mice is now an easy task and can be achieved relatively rapidly. A first challenge is to
accelerate the development/translation from POC in mice to clinical trials in LD patients. This requires to evaluate
efficiency and safety issues (adverse effects due to overexpression, off-target expression of therapeutic gene) in large
animals, in particular non-human primates. This is very costly and requires special platforms. The last challenge is the
cost needed to set-up full Good Manufacturing Practice (GMP) phase I/III trials. This is not specific to LDs and concerns all
inherited rare disorders. It requires partnership with the pharmaceutical industry.

Perspectives on Ethical issues
In Leukotreat, ethical issues were investigated (i) to achieve a better understanding of patients and families’ expectations
and needs regarding the setting-up of the LeukoDataBase, (ii) to promote partnerships between the public (patients and
families) and researchers, (iii) to promote best practices in research on rare diseases. Documents such as the
LeukoDataBase Charter and Patients’ information documents have been made public to foster knowledge sharing
between EU projects. According to the results from the LeukoTreat survey, three directions should be further investigated
regarding ethical issues:
• The added value of patients’ contribution to the LeukoDataBase should be further evaluated as not enough data were
collected during the project lifetime.
• More information should be delivered to patients and their families.
• There is more work to be done on handling the ethical issues linked to patient recruitment in clinical trials at the EU
level, especially regarding communication with the patients and their families. The work was performed in partner
countries that have existing national databases. There is a need for an ethical survey, as other countries will join.
57
For more information
visit us at www.leukotreat.eu
58
www.leukotreat.eu
59

one with a scientific orientation

Transcription

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