Transcript Professor Orla Hardiman - Genetic and Rare Disorders Organisation

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?
• “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
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
Solutions
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Population based Registers
Centralized care
Orphan drug legislation
Advocacy
Clinical Research
in Rare Diseases
• Applied epidemiology
– Databases and Registers
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Good clinical monitoring with attention to detail
Determination of relevant clinical questions
Phenotype genotype correlations
Biomarkers
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
Imperatives for Valid and
Clinically Relevant Study
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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
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
Lou Gehrig
1903 - 1941
Irish Register of Motor Neurone
Disease
• Commenced in 1993
• Ascertainment complete by 1995
• First epidemiologic data analysed for 19951997; Second 2005-2007
• Data collection ongoing: >1400 patients
enrolled to date
Experiences of the Irish Register
over 15 years
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Basic epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Complex Genetics
Comparison with other population
WORLD EPIDEMIOLOGY
OF ALS/MND
Population Based Incidence of
ALS/MND
Incidence per 100,000 (age 45-75)
12
10
8
6
4
2
0
Ireland
Scotland
Tx.,USA Wa.,USA Mn.,USA Denmark
Israel
Finland
Sardinia
On,
Canada
Sweden
Traynor et al, 1999
True incidence and prevalence outside predominantly
Caucasian populations not widely known
N.
Sweden
IRISH MND
Experiences of the Irish Register
over 15 years
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Basic epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Complex Genetics
Comparison with other populations
Age related Incidence Rates of ALS
1997-2004
Incidence per 100,000 person-years
12.0
10.0
8.0
male limb
male Bulbar
Female Limb
6.0
female bulbar
4.0
2.0
0.0
0-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age group (years)
SURVIVAL FROM MND
Survival Effect of Multidisciplinary
Clinics
1
.8
Cum. Survival (general)
n = 258 pts.
.6
Cum. Survival (multidisciplinary) n = 108 pts.
.4
.2
0
0
.5
1
1.5
2
2.5 3 3.5 4
4.5
Time from diagnosis (years)
Survival
Republic of Ireland v Northern Ireland
Uses of the Irish Register of ALS
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Comparative epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Complex Genetics
Comparision with other populations
Uses of the Irish Register of ALS
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Comparative epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Complex Genetics
Comparison with other populations
Longitudinal Follow up
Younger, Higher education
and FSIQ
Older, Aggressive
Disease
Early Executive
involvement
With time they develop
Slow motor progression
Small proportion develop
abnormalities: mostly
language or verbal fluency
deficits
language/memory/VP
FTD
Early memory and language
difficulties
± subtle executive changes
More Benign course initially
High rate of developing
executive dysfunction
Uses of the Irish Register of ALS
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Comparative epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Genetics
Comparison with other populations
FINDING FAMILIES
Manifestation definitions :
Amyotropic Lateral Sclerosis
Fronto Temperol Demetia
Pneumonia
Stroke
Congenital Cardiac Failure (CCF)
Depression
TB
Finding Genes
16 causative genes known, accounting
for ~15% of all MND
Separating the Population by
Causative Genes
Lancet Neurology 2012
Uses of the Irish Register of ALS
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Comparative epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Population Genetics
Comparison with other populations
Looking for Susceptibility Genes
Genes of small effect that may
contribute to risk
Population Structure Within Europe
(Novembre et al Nature 456 ; 6 , 2008)
IRISH POPULATION ALSO DEMONSTRATES
GENETIC SUBSTRUCTURE:
Comparison With Dutch & US populations
Simon Cronin PhD Thesis
Irish Population is Relatively
Homogeneous
• Modern Ireland is derived from a restricted
founding population with a higher degree of
relatedness
Angiogenin Mutations Are Associated
with ALS
Nature Genetics 2006 38:4:411-12
Uses of the Irish Register of ALS
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Comparative epidemiology
Long term follow up of population
Accurate recording of clinical details
Identification of defined clinical subtypes
Complex Genetics
Comparison with other populations
EURALS
(N= 25 million)
EURALS: The Incident Cases
Scotland
Puglia
130
231
194
154
265
54
Ireland
Lombardia
Piemonte
Lancashire
N=1028
DRUG TRIALS
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
Research Team and Collaborators
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Clinical Epidemiology & Neuropsychology
Cuban Collaborators
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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.Tatiana Zaldivar
Dr.Joel Gutierrez
Dr. Gloria Lara
Dr.Diana Garcia del Barco
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Dr.Giancarlo Logroscino
Previous Research Fellows
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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)
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)
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
FURTHER INFORMATION
RESEARCH MOTOR NEURONE
www.mnd.ie