Dr. José M. Millán, PhD Deputy Director of CIBERER Universitary Hospital La Fe, Valencia, Spain

1. Barriers and Challenges in Rare Diseases Research Centre for Biomedical Network Research on Rare Diseases (CIBERER)A model of cooperative and translational research on rare diseases Dr. José M. Millán, PhD Deputy Director of CIBERER Universitary Hospital La Fe, Valencia, Spain Dublin March 26, 2012

2. Research in Rare Diseases in Spain Historial Overview • 1996. Creation of CISAT (Centre fortheResearch of theToxicOil) in theInstitute of Health Carlos III (ISCIII) • 2000. RareDiseases are includedby ISCIII as a MainTopicforitsResearchProgramme. • 2001. CISAT becomes CISATER (Centre fortheResearch of theToxicOil and RareDiseases). Creation of SIERE (Service of InformationonRareDiseases in Spanish). • 2003. RETICs (Networks forThematicResearch): REpIER, INERGEN y RECGEN (Oneepidemiologicalnetwork and twogeneticresearchnetworkson RD. CISATER isthennamed IIER (InstituteforResearch in RareDiseases • 2006. CIBERER (Centre for Biomedical Network Research on Rare Diseases)

3. PrioritaryBiomedicalResearchTopics • CNIO: National Centre forOncologyResearch • CNIC: National Centre for Cardiovascular Research • CIBERS: • CIBERNED: Neurodegenerative disorders • CIBERES: Respiratory disorders • CIBERHED: Hepatic and digestive disorders • CIBEROBN: Obesity and Nutrition • CIBERDEM: Diabetes and associated metabolic disorders • CIBERBBN: Bioengineering, Biomaterials and Nanomedicine • CIBERER: Rare Diseases • CIBERESP: Epidemiology and Public Health • CIBERSAM: Mental Health

4. 2009. StrategyforRareDiseases of theNationalHealthSystemMinistry of Health and Social Policy Coordinator: Prof. Francesc Palau • Needs: • Information • Prevention and Early Diagnosis • Health and Social Care • Therapy • Research • Training

5. Barriers in Rare Diseases Research Epidemiology • Lack of knowledge, lack of information • Deficientorinexistenthealthregistriesformanyrarediseases and difficultcodingaccordingtothe ICD system of classification • Difficultiesforepidemiologicalstudies • Visibility • Toidentifythecurrenthuman and informationresources • To set up registriesforeachraredisease and forrarediseases as a global problem • Toascertainthemedical/ economicalburden of rarediseases • Beware of Dr. !!

6. Barriers in Rare Diseases Research Basic and ClinicalResearch Natural History, Physiopathology, Genetics, DiseaseModels... • Thebudgetforbiomedicalresearchin Spainislowcomparedtoother EU countries (0.9% GDP) • Thebudgetforrarediseasesislowcomparedtocommondiseases • Tostimulatefuture R&D projectswithintheHealthStrategicActions • Topromotethepriorization of researchprojectsonrarediseases • Tocreate, maintain and improvenecessarystructures, facilities and humanresources

7. Barriers in Rare Diseases Research Therapy • Lack of interest of thePharmaindustry (toomuchinvestmentfortooloweconomicalbenefit) • Veryfewemergingsmallcompaniesinterested in • Notmanylaboratoriesworking in therapiesforrarediseases • Topromoteinterest and financialsupportfromthePublicHealthSystem and Pharmaenterprises • CollaborationwithPharmaIndustry and Biotechs • Topromoteresearch in orphandrugs - advancedtherapies (gene-basedtherapy and celltherapy)

8. Barriers in Rare Diseases Research Training • In Spainthereisnot a formal specialtyin ClinicalGenetics • Rarediseases are not a topic in Universities, Medicine Schools... • Students and scientist are more pronetocommondiseases (Cancer, AIDS, Alzheimer dis., Cardiovascular dis...) • Difficulties in making a carrier in genetics and rarediseases • Creation of thespecialtyin ClinicalGenetics (forphysicians, biomedicalsciences, psicology...(AEGH and CIBERER) • Courses, masters, academictopicsdevotedtorarediseases

9. Why research on rare diseases is needed? • Social reasons • Medical reasons • Scientific reasons

10. National Centres of Expertise (CoE) • Clinical investigation/Basic research • National research networks • Databases, registries, biobanks, • epidemiological surveillance • Pharmaceuticals and biotechs Multidisciplinary and Integrative approach Rare Diseases Research Supranational collaboration • European Networks of CoE, ECN • European policy: fostering • national plans • European platforms & infrastructures • Patient empowerment CIBERER: An integrative proposal Human factor Financial factor Training factor Research groups Society Healthcare system Social factor Political factor

11. Centre for Biomedical Network Research on Rare Diseases (CIBERER) CIBERER is a public consortium set up at the initiative of the Institute of Health Carlos III (ISCIII) to act as a reference to coordinate and foster research into Rare Diseases in Spain. CIBERER groups clinical and basic researchers promoting Cooperative Research. The knowledge generated is translated from the laboratory to clinical practice, and vice versa: Translational Research. CIBERER provides strategic coordination, human resources and materials as well as a collaborative environment where synergy proper to high multidisciplinary and complementary research potential can be developed. The CIBERER has large human resources - over 700 persons, made up of its own staff of 159 CIBERER contracted researchers, the rest of the members of the groups being scientists and technicians attached to CIBERER. 53% of ourpersonnel are PhDassociateresearchers.

12. Organization Chart of the CIBERER Governing Board External Advisory Scientific Committee Permanent Commission Scientific Director ManagementCommittee (Coordinators) Management Office Associated Clinical Groups ResearchProgrammes: ThematicMedicalProgrammes Paediatric and Developmental Medicine Neuro-sensorial Pathology Inherited Cancer and Related Syndromes Genetic Medicine InheritedMetabolic Medicine Mitochondrial Medicine Endocrine Medicine Intramural Biomedical Projects in Rare Diseases (PIBER) Intramural Projects and Support Platforms Support Platforms for Research into Rare Diseases (PITER)

13. Cooperative research in the field of rare diseases CIBERER units are organized into seven Research Programmes:

14. Internal Structure of CIBERER • 60 Research Groups 29 Consorted Institutions 7 Research Programmes • The centre encloses clinical and basic researchers promoting Cooperative Research in Rare Diseases. • It is a Centre with an innovative network structure: offers opportunities of research actions and public-private collaboration. • The knowledge generated is translated from the laboratory to clinical practice • Translational Research

15. Cooperative research in the field of rare diseases • During its 5 years of existence, the CIBERER has allowed increasing the research capacity of its scientific groups and has increased the knowledge about Rare Diseases. CIBERER Programmes have: • Joined and increased the Cooperation between basic and clinical units • Increased the Research on Rare Diseases • Fostered the Participationof groups in the CIBERER’s programmes • Established Institutional Relations • Promotedand Disseminated the activities of groups • Fostered the International Cooperation opportunities of groups BIER BioInformatica de Enfermedades Raras Network core facilities

16. CIBERER´s therapeutic research • Examples of intramural cooperative research projects • Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Raya et al. CIBERER Units 710 & 745. Nature. 2009 May 31 • Transplantation of histocompatible allogeneic epidermal stem cells: Development of an effective clinical resource for patients with dystrophic epidermolysis bullosa. • INTRA/08/714,1. • Gene therapy in Dyskeratosis congenita • INTRA/08/757,1. CIBERER Units 757 & 710 • Evaluation of the immune response and oxidative stress in patients affected by Gaucher disease subjected to different forms of therapeutic treatment. • INTRA/08/752.2. CIBERER Units 752 & 719 Cooperation with the Spanish Biotech Stakeholders Association (ASEBIO) Collaboration with specific preclinical research actors Agreement with Medina Foundation: non-profit public–private partnership between Merck Sharp and Dohme and public institutions focused on the discovery of new compounds and innovative therapies for unmet medical needs CIBERER member of Innovative Medicaments working group

17. Experimental models in rare diseases: towards preclinical research • The approach is to establish scientific collaborations with experts from others academic research groups, biotech and pharmaceutical companies interested in testing their compounds and their panels of target screens in specific rare diseases models. • CIBERER experimental models network resources: • 91 animal models for the study of rare diseases: • Mouse, Zebrafish, Drosophila, Medaka, C. elegans. • 59 cells models for the study of rare diseases: • HeLa, 3T3, SH-S5SY neuroblastoma cells, fibroblasts, COS cells, lymphoblast cells, astrocytes… • Example of animal models: • McArdledisease (Pygm) • X-linkedadrenoleukodystrophy (Abcd1) • Charcot-Marie-Toothtype 4A (Gdap1) • Retinitis pigmentosa(Cerkl) • Down syndrome(Dyrk1a, others) • Laforadisease(malin, laforine) • Etc.

18. 2007 -2011: an increase of the scientific collaboration and productivity by the CIBERER groups Evolution of intramural collaboration - CIBERER 2000-02 and 2006-08

19. 2007 -2011: an increase of the scientific collaboration and productivity by the CIBERER groups Intramural collaboration – CIBERER 2010

20. 2007 -2011: an increase of the scientific collaboration and productivity by the CIBERER groups Collaborative network of CIBERER groups with other Spanish institutions (240) Collaborative network of CIBERER groups with other international institutions (742)

21. Outcomes: increase on the number and quality of papers in RD Publications output between 2005 - 2010

22. Outcomes: increase on the number and quality of papers in RD Evolution of the papers distribution of CIBERER groups based on JIF (Journal Impact Factor) parameters

23. “A model of Cooperative Research on Rare Diseases” GoraibhmaithagatThankyou More Information: www.ciberer.es info@ciberer.es (+34) 96.339.47.89