Insights into successful Research in Rare Diseases

Work by the Irish Motor Neurone Disease Research Group

Orla Hardiman BSc MD FRCPIHRB 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

• Population based Registers

• Centralized care

• Orphan drug legislation

• Advocacy

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

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

• 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 Gehrig1903 - 1941

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

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

WORLD EPIDEMIOLOGY OF ALS/MND

Population Based Incidence of ALS/MND

0

2

4

6

8

10

12

Ireland Scotland Tx.,USA Wa.,USA Mn.,USA Denmark Israel Finland Sardinia On,Canada

Sweden N.Sweden

Incid

ence p

er

100,0

00 (

age 4

5-7

5)

True incidence and prevalence outside True incidence and prevalence outside predominantly Caucasian populations not predominantly Caucasian populations not widely knownwidely known

Traynor et al, 1999

IRISH MND

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

Age related Incidence Rates of ALS1997-2004

0.0

2.0

4.0

6.0

8.0

10.0

12.0

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+

Inc

ide

nc

e p

er

10

0,0

00

pe

rso

n-y

ea

rs

Age group (years)

male limb

male Bulbar

Female Limb

female bulbar

SURVIVAL FROM MND

Survival Effect of Multidisciplinary Clinics

0

.2

.4

.6

.8

1

0 .5 1 1.5 2 2.5 3 3.5 4 4.5Time from diagnosis (years)

Cum. Survival (multi-disciplinary) n = 108 pts.

Cum. Survival (general)n = 258 pts.

Survival

Republic of Ireland v Northern Ireland

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

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

Longitudinal Follow up

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

Younger, Higher education and FSIQ

Slow motor progression

Small proportion develop abnormalities: mostly language or verbal fluency deficits

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

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

• 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

• 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

N=1028Piemonte

Lombardia

PugliaScotland

Ireland

Lancashire

231

15454265

194

130

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• 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 CollaboratorsDr.Tatiana ZaldivarDr.Joel GutierrezDr. Gloria Lara Dr.Diana Garcia del Barco

Previous Research FellowsDr.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