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Insights into successful Research in Rare Diseases

Insights into successful Research in Rare Diseases. Work by the Irish Motor Neurone Disease Research Group Orla Hardiman BSc MD FRCPI HRB Clinician Scientist Trinity College & Beaumont Hospital Dublin. What is a Rare Disease?.

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Insights into successful Research in Rare Diseases

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  1. Insights into successful Research in Rare Diseases Work by the Irish Motor Neurone Disease Research Group Orla Hardiman BSc MD FRCPI HRB Clinician Scientist Trinity College & Beaumont Hospital Dublin

  2. What is a Rare Disease? • “Life-threatening or chronically debilitating diseases which are of such low prevalence (fewer than 1 in 2,000) that special combined efforts are needed to address them.“ European Commission on Public Health

  3. Problems with Studying Rare Disease • They are rare! • Knowledge deficit • Delayed diagnosis • Low quality of care • Limited access to new drugs. • Cost of drug development • Cost of post-approval drugs

  4. Solutions • Population based Registers • Centralized care • Orphan drug legislation • Advocacy

  5. Clinical Research in Rare Diseases • Applied epidemiology • Databases and Registers • Good clinical monitoring with attention to detail • Determination of relevant clinical questions • Phenotype genotype correlations • Biomarkers

  6. Advantages of Population Based Registers • More accurate reflection of range of disease phenotypes • Nobody is “lost to follow-up” • Captures patients that might not attend specialist clinic • Too old • Too sick • Too poor

  7. Imperatives for Valid and Clinically Relevant Study • Prospective study of incident cases • Adequate sources • “Capture recapture” methodology • Standardisation of population demography • Large numbers over sufficiently long follow up period • Attention to clinical detail

  8. Lou Gehrig 1903 - 1941 Motor Neuron Disease • Commonest neurodegeneration of young and middle aged adults • Incidence 2.6/100,000 • Prevalence: 1in 16,000 • Lifetime risk 1:400 • Unknown aetiology • 10% familial • Fatal within 3-5 years • No cure

  9. Irish Register of Motor Neurone Disease • Commenced in 1993 • Ascertainment complete by 1995 • First epidemiologic data analysed for 1995-1997; Second 2005-2007 • Data collection ongoing: >1400 patients enrolled to date

  10. Experiences of the Irish Register over 15 years • Basic epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Complex Genetics • Comparison with other population

  11. WORLD EPIDEMIOLOGY OF ALS/MND

  12. Population Based Incidence of ALS/MND Traynor et al, 1999 True incidence and prevalence outside predominantly Caucasian populations not widely known

  13. IRISH MND

  14. Experiences of the Irish Register over 15 years • Basic epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Complex Genetics • Comparison with other populations

  15. Age related Incidence Rates of ALS1997-2004

  16. SURVIVAL FROM MND

  17. Survival Effect of Multidisciplinary Clinics

  18. Survival Republic of Ireland v Northern Ireland

  19. Uses of the Irish Register of ALS • Comparative epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Complex Genetics • Comparision with other populations

  20. Uses of the Irish Register of ALS • Comparative epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Complex Genetics • Comparison with other populations

  21. Longitudinal Follow up

  22. Younger, Higher education and FSIQ Slow motor progression Small proportion develop abnormalities: mostly language or verbal fluency deficits Older, Aggressive Disease Early Executive involvement With time they develop language/memory/VP FTD Early memory and language difficulties ± subtle executive changes More Benign course initially High rate of developing executive dysfunction

  23. Uses of the Irish Register of ALS • Comparative epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Genetics • Comparison with other populations

  24. FINDING FAMILIES

  25. Finding Genes 16 causative genes known, accounting for ~15% of all MND

  26. Separating the Population by Causative Genes Lancet Neurology 2012

  27. Uses of the Irish Register of ALS • Comparative epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Population Genetics • Comparison with other populations

  28. Looking for Susceptibility Genes Genes of small effect that may contribute to risk

  29. Population Structure Within Europe (Novembre et al Nature 456 ; 6 , 2008)

  30. IRISH POPULATION ALSO DEMONSTRATES GENETIC SUBSTRUCTURE: Comparison With Dutch & US populations Simon Cronin PhD Thesis

  31. Irish Population is Relatively Homogeneous Modern Ireland is derived from a restricted founding population witha higher degree of relatedness

  32. Angiogenin Mutations Are Associated with ALS Nature Genetics 2006 38:4:411-12

  33. Uses of the Irish Register of ALS • Comparative epidemiology • Long term follow up of population • Accurate recording of clinical details • Identification of defined clinical subtypes • Complex Genetics • Comparison with other populations

  34. EURALS (N= 25 million)

  35. EURALS: The Incident Cases Scotland Puglia 130 231 194 154 54 265 Ireland Lombardia Lancashire Piemonte N=1028

  36. DRUG TRIALS

  37. RESEARCH INTO RARE DISEASES….. Permits complete population based incidence & prevalence studies • Identifies prognostic indicators • Identifies subpopulation that can help to find new genes/ susceptibility factors • Informs health services • Facilitates international collaborations • Provides well characterized populations for clinical trials

  38. Research Team and Collaborators Clinical Epidemiology & Neuropsychology Dr.Marwa Elamin (Beaumont & TCD) Dr.Niall Pender (Beaumont &TCD) Ms.Catherie Lynch (Beaumont) Dr.Peter Bede (Beaumont & TCD) Dr.Susan Byrne (Beaumont &TCD) Dr.Colin Doherty (St.James & TCD) Dr.Giancarlo Logroscino EURALS Steering Group (Europe) Genetics , Prof.Dan Bradley (TCD) Mr.Russell McLaughlin (TCD) Mr.Kevin Kenna (TCD) Prof.Leonard Van Den Berg (Utrecht) Prof.Angnieska Slowik (Krakow) Prof.RH Brown Jr. (MGH Boston) Prof.Peter Andersen (Umea, Sweden) Cuban Collaborators Dr.Tatiana Zaldivar Dr.Joel Gutierrez Dr. Gloria Lara Dr.Diana Garcia del Barco Previous Research Fellows Dr.Bryan J Traynor (NIH) Dr.Mike Alexander (LONDON /DUBLIN) Dr.Orna O’Toole (DUBLIN / NEW YORK) Dr.Matthew Greenway (TORONTO) Dr.Julie Phukan (LONDON)

  39. FUNDING SOURCES • Health Research Board • Irish Motor Neurone Disease Research Foundation • Irish Motor Neurone Disease Association • Irish Institute of Clinical Neuroscience • Muscular Dystrophy Association USA • American ALS Association

  40. FURTHER INFORMATION RESEARCH MOTOR NEURONE www.mnd.ie

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