mnd research in ireland

MND RESEARCH IN IRELAND

Time for Optimism

Orla Hardiman BSc MD FRCPI FTCD MRIAProfessor of NeurologyTrinity College Dublin

IRELAND IS A LEADING INTERNATIONAL RESEARCH

HUB IN MND

TRINITY COLLEGE DUBLIN • 50+ brilliant young researchers• World class science• 20+ PhDs in the past 10 years• Innovative cross-disciplinary projects

– Neurological evaluation– Neuropsychology– Epidemiology– Genetics– Neural Engineering– Mathematics– Statistics– ICT Platform technology – Health Services Research – Burden & Health Economic outcome– New Drug Development – Clinical Trials

Mark Heverin Research Manager

OBJECTIVE

To understand the causes of MND to the extent that we can develop new and

more effective treatments .

WE INVEST IN TALENT AND EXCELLENCE

Miriam Galvin, Assoc Professor in Research Methods

Niall Pender, Assoc Professor in Neuropsychology

Peter Bede, Professor in Brain Imaging

Russell McLaughlin Ussher Assistant Professor,ALS/MND Genomics

Bahman Nasserelsoslami, Fr.Tony Coote Assistant Professor in ALS/MND

Dara Meldrum, Assoc Professor in Clinical Measurement, Deirdre Murray, Assist. Prof in Clinical Measurement

SOME OF OUR WORK… • First to provide a sustainable population based register in ALS &ALS/FTD (27 years)• Acknowledged leadership in population based Register design• First to show that ancestral origin is an important risk in ALS• First to show survival benefit of multidisciplinary clinics • First to show using population data that heritability is high in ALS (0.53)• First to fully describe the population based relationship between ALS and Dementia• First to demonstrate expanded phenotype in C9orf72 related disease • Found important new genes in ALS/MND ANG, NEK1,• Discovered and proved an important biological link between ALS/MND and

Schizophrenia using epidemiology and genomics• Demonstrated new data driven patient subgroups using of brain imaging and signal

analysis• First to Deconstruct measurement scales showing-major floor & ceiling effects • First to validate ECAS & to generate & validate a new ALS Specific behavioural scale • Development of clinical meaningfulness attributes • Development of detailed Caregiver Burden Data• New system for using EEG to measure change in brain function in MND

CURRENT STATE OF THE ART IN

IRISH MND RESEARCH

ALS: A Gene-environment Interaction(in 6 steps)

Hardiman & Al-Chalabi Nat Rev Neurol 2013Al-Chalabi et al Lancet Neurol 2015Chio et al Neurology 2018

3-5 additional events

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Heritability overall population

Overall Daughter-mother Son-mother Daughter-father Son-father

Heritability Estimates using the Irish ALS/MND Register

Genetics account for approximately 50% of the risk of developing MND (at population level)

JAMA Neurol. 2019 Nov 1;76(11):1367-1374.

THE HUNT FOR GENES

GENES ASSOCIATED WITH ALS

Gregory, J.M et al . Curr Genet Med Rep 8, 121–131 (2020)

30 GENES OF MAJOR EFFECT

Not All Gene “mutations” cause disease!

alsftd.tcd.ie Mark Doherty & Russell McLaughlin

CAUSES OF MND: CURRENT CONCEPTS

UNDERSTANDING THE CAUSE OF DISEASE CAN INFORM NEW DRUG

DEVELOPMENT

SOD1 TRANSGENIC ANIMAL MODEL

– Does the drug work?– Is the drug toxic?

LESSONS FROM THE SOD1 MOUSE

MANY GOOD DRUGS FAIL IN THE “VALLEY OF DEATH”

Mouse Problems

• Animal models useful but limited…

– Anatomy differs– Genetic background important: “strain effect”– Gender Differences– Effects of multiple copies of an inserted human

gene

– (DIFFERENT PATHOLOGY..)

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ALS mSOD1 Transgenic Mice

Human MND

Of Mice and Men: Homogeneity versus Disease Onset and Progression

THE TRANSLATION PROCESS ISN’T WORKING….

MMD:A COMPLEX HUMAN DISEASE

SPECTRUM

“Pure”ALS

ALS and Dementia

15%

ALS and Behavioural Impairment

HUMAN MNDNOT JUST MOTOR NEURONS

ALS and Cognitive Impairment

Up to 35%Up to 70%

No abnormality detected

47%

Executive Dysfunction21%

Non-executive Cognitive Impairment

14%

ALS-FTD14%

Comorbid Alzhemier's Disease 2%

Neurology Clinical Practice 2020

J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):102-8.

Behaviour Classifications

Factor Loading

Superordinate Classification of

Dysfunction

Cognitive/Behavioural Dysfunction

1 Initiation (Apathy) Loss of interest; inability to plan; impulsiveness; decreased sex drive; lack of appropriate embarrassment.

2 Adherence to social norms

Emotional changes; social disinhibition; social seeking.

3 Social Engagement Social withdrawal; distractibility; cognitive rigidity.

4 Interpersonal Engagement

Aggressiveness; irritability; Increased lability; hypersensitivity to stimuli.

5 Self-regulation Reduced concern for hygiene; change in food preferences; new onset repetitious/obsessive behaviour.

Elamin M et a; Identifying behavioural changes in ALS: Validation of the Beaumont Behavioural Inventory (BBI). Amyotroph Lateral Scler Frontotemporal Degener. 2017 Feb;18(1-2):68-73

MND AND FRONTOTEMPORAL DEMENTIA ARE PART OF A SPECTRUM

MND IS MORE THAN ONE CONDITION

PRECISION MEDICINE

PRECISION MEDICINEPrecision Medicine refers to the tailoring of medical treatment to the individual characteristics of each patient…..It relates to the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment.

ARE THERE KNOWN ENVIRONMENTAL RISKS?

EUROMOTOR studyLAENALS studyMetALS study

Environmental “exposures” very are hard to detect

We need very big numbers, and combinations of different types of data

WHAT CAN WE LEARN FROM “FAMILIAL” MND IN IRELAND?

KNOWN GENES

• C9orf72 accounts for 30-50% of known “familial” ALS in European populations

In Ireland up to 20% of people with ALS have another family member

with MND or FTD

50% of these kindreds carry the C9orf72 repeat expansion

…WHAT ELSE ARE WE MISSING… ?

ALS

Frontotemporal dementia

Psychosis

Impulse dyscontrol

Autism

Bipolar disorder

Other Related Conditions in some MND Families

OCD

O’Brien et al, JAMA Neurol 2017 Dec 1;74(12):1425-1430.

Alcohol overuse

“SUPERFAMILIES”

Summary So Far..

• Studying family members of those with MND has shown us that there is a link between some forms of MND and some psychological (and psychiatric) traits

• This link is probably related to how different brain networks operate

• Understanding these links will help us to better understand MND and to find better treatments

CONCEPTUAL SHIFT:

MND IS A HUMAN SYNDROME THAT IS BEST UNDERSTOOD AS ADISORDER OF BRAIN NETWORKS

BRAIN IMAGING

CAN RELIABLY DEMONSTRATE EXTRA-MOTOR INVOLVEMENT IN REGIONS THAT PREDICT COGNITIVE /BEHAVIOURAL CHANGE

MRI CHANGES IN MND

APPLIED BRAIN WAVE ANALYSIS (EEG)

Finding different patterns of brain network disruption in MND:

Can help to find subgroups and to decide if a drug is working

Human Brain Mapping 2019

Characteristic patterned changes of brain wave activity identifies brain network disruption

Trinity College Dublin, The University of Dublin University Medical Centre Utrecht

PATTERNED NETWORK CHANGES IDENTIFY DISEASE SUBGROUPS

Clinical profiles

Dukic et al, Brain 2021 (In press)

ACTIVATING DIFFERENT BRAIN NETWORK PATTERNS

MISMATCH NEGATIVITY (MMN) STUDIES

Trinity College Dublin, The University of Dublin

Harnessing source localisation to study ALS

Iyer et al., 2017

The Mismatch Negativity Response

Involuntary attention switching Mismatch negativity wave

Trinity College Dublin, The University of Dublin

THE SUSTAINED ATTENTION TO RESPONSE TASK (SART)

Response inhibition upon number 3

3

Robertson et al., 1997

• Motor and cognitive task

• Behavioural results alone insensitive to early ALSci

• EEG measures can determine cognitive/motor subdomains and regions affected

IRISH MND RESEARCH INTHE

EUROPEAN CONTEXT

Treatment Research Initiative to Cure ALS

The TRICALS consortium

UKNetherlandsIrelandItalySwedenFranceSpainBelgium

TRICALS: a consortium that delivers

• ENCALS• Generating international standards & biobanks

– SOPHIA Biomarkers– EuroMotor Pan-European database, -omics– STRENGTH Genetics, lifestyle & environment– NETCALS Patient cohorts– BRAIN-MEND Disease clustering– ALS-CarE Patient care journeys

• Project MinE• Progeny: harmonized, shared database

MISSION

THE RIGHT DRUG, FOR THE RIGHT

PATIENT, IN THE RIGHT DOSE, AT THE

RIGHT TIME

FINDING MORE GENES

Capitalising on Project Mine

Unites researchers and fundraisers

18+ Million raised in 17 countries

10,605 genomes sequenced

Expanding globalcollaboration

Translate genetics to clinical studies

OBJECTIVES

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1. Combine different European datasets to reveal subgroups of patients

2. Develop and implement single set of biomarkers to measure disease progression

3. Improve clinical trial design to best test noveltreatments in distinct subgroups

4. Develop a pan-European platform to collect data and coordinate clinical studies

5. Develop (patient reported) outcome measures to assess cost-effectiveness of new therapeutics

Highway to therapy

REALTIME DATA UPLOADS for TRIAL READINESS

A pan-European Electronic Patient Record

BETTER ACADEMIC/INDUST

RYCOLLABORATION

REAL WORLDDATA ANALYTICS "BETTER TRIALS " BETTER CLINICAL

OUTCOMESEDUCATION(BIG DATA)

HEALTHECONOMICS

LARGEPATIENT COHORTS

CLUSTERINGOF PATIENTS

NOVEL BIOMARKERS(IMAGING/ SIGNAL

ANALYSIS)

GENE BASED THERAPIES CAREGIVER DATA SURVIVORSHIP

ANALYSES

REAL WORLD DATA CLINICALMEANINGFULNESS

NOVELBIO-MARKERS

(WET)

NOVELOUTCOME MEASURES

BETTER CAREPATHWAYS

NOVELTELEMEDICINE

CLINICALEVALUATION

(PHENOTYPING)

DIGITAL OUTCOMEMEASURES COGNITION EXISTING "WET"

BIO-MARKERSDRUG TREATMENTS

REMOTE MONITORING

IMAGING(MRI)

NEUROELECTRIC SIGNAL

ANALYSIS

PATIENTPORTAL

CAREGIVERPORTAL ENABLING

DEVICES

PRIARY LATERAL SCLEROSIS

SOCIETAL BENEFITS

PRECISION MEDICINE CLINICAL TRIALS

MACHINE LEARNING

DATA ANALYTICSMULTIMODAL

PLATFORMDATAPATIENT CHARACTERISTICS

DATA MANAGEMENT

GOVERNANCE

DISEASE FOCUS

AMYOTROPHIC LATERAL SCLEROSIS

PROGRESSIVE MUSCULAR ATROPHY

PROGRESSIVE BULBAR PALSY

GENOMICS

BEHAVIOURAL VARIANT FTD

PRECISION ALS

WHAT ABOUT CLINICAL TRIALS?

MND TRIALS: The Past

• > 40 negative trials• Animal-based approach has not been

successful • Effective treatments likely to be in subgroups

of patients• Better biomarkers required • Trial design and outcome measures need to

be refined

Over 20 compounds now in late pre-clinical phase

NEW “DESIGNER” TREATMENTS

• Based on genetics– Anti-sense oligonucleotides

•SOD1•C9orf72 repeat expansion

MORE NEW TRIALS (Starting this year)

• MERIDIAN • ADORE • COURAGE • PHOENIX • LIGHTHOUSE• MAGNET

TAKING CARE OF ALL THOSE WITH MND

The Importance of a National Multidisciplinary Clinic

IMPROVING THE PATIENT PATHWAY

PATIENT centricCAREGIVER centric

• Understanding experiences of the illness beyond the disease pathology

• Patients and caregivers as collaborative partners• Attribution of clinical meaningfulness• Incorporation of patient reported outcomes• Appropriate applications of user-friendly

technology

Private & confidential

UNDERSTANDING THE NEEDS OF CAREGIVERS

Partnering with the Patient and Caregiver:

A Novel approach to deliver clinically meaningful benefits

Integrating Digital Healthcare Technology to Reduce Burden of

Evalution

01/10/2021 © The University of Sheffield

TELEMEDICINE IN MND

CONCLUSIONS

• Irish MND research is at the cutting edge and has made many important discoveries

• The Irish MND Research team works closely with all major European centres as part of the TRICALS Consortium : Together we will find new and more effective treatments

• The Research team is grateful to all Irish people with MND families for their generosity in helping us to understand this condition & to find new treatments

• The Research team is grateful to the IMNDA for their unwavering support over the past 30 years

Team Applied ClinicalBernie CorrAisling O’ReillyOlivia GroganTrion MannermanDr.Deirdre MurrayDr.Dara MeldrumMairead CampbellLesley DoyleKitty McElligott

Imaging & EEGDr.Peter BedeDr.Bahman Nasseroleslami Dr.Róisín McMackinDr.Eoghan FinneganDr.Amina CoffeyStefan DukicSaroj Bista

NeuropsychologyDr.Niall PenderDr.Marta PintoDr.Marwa ElaminEmmet Costello

EpidemiologyDr.Marie RyanDr.James RooneyColm Peelo

Genetics Prof Dan BradleyDr.Russell McLaughlinDr. Kevin KennaDr. Ross ByrneMark Doherty

Academic NeurologySara Batsukh

Health ServicesDr. Miriam GalvinDr.Sinead Maguire

EMG & BiomarkersDr.Amina Coffey Dr.Lara McManus

Clinical TrialsLiz FogartyDr. Sinead MaguireDr.Amina CoffeyDr.Sarah Darcy

Research ManagerMark Heverin

Laboratory/NeuropharmDr. Julie Kelly

RESEARCH FUNDING