Rare Disease Day 2015 Conference Day 2: Heather Durham

1. E-RARE PROJECT “RNA-ALS”
CORD: RARE DISEASE DAY CONFERENCE
2015
Heather D. Durham, PhD
Montreal Neurological Institute
McGill University

2. What is E-RARE?
• ERA-Net for Research
Programmes on Rare
Diseases
– transnational funding of
collaborative,
multidisciplinary and
ambitious projects on rare
diseases
– leveraged funding for rare
disease research in
participating countries
(and other organizations)
• Canada (E-RARE 2)
– CIHR: Institute of
Genetics
– FRSQ (Quebec)
– Health Charities (ALS
Canada, etc.)

3. E-RARE Calls
• 7 joint calls for research projects on rare diseases since 2007
• Each specifies general topic areas for proposals and the countries and
organizations participating
• Rare neurological diseases are now covered under the Programming
Initiative on Neurodegenerative Disease Research (JPND;
http://www.neurodegenerationresearch.eu/).
• Requirement for 3-8 partners from at least 3 participating countries
RNA-ALS
Canada: Heather Durham from McGill & Michael Strong from Western
(CIHR-IG, FRSQ, ALS Canada)
France: Edor Kabashi from Institut du Cerveau et de la Moelle Epinière
(l’Agence nationale de la recherche - ANR)
Israel: Eran Hornstein, Weizmann Institute
(State of Israel Ministry of Health – CSO/MOH)

4. Why RNA-ALS?
What is ALS?
Clinical Presentation
Weakness and muscle atrophy:
Limbs
Bulbar involvement – fast progression
Respiratory
Difficulty swallowing, speaking, breathing
Fatigue
Muscle cramps
Fasciculations: tongue and limbs
Upper motor neuron (pyramidal) signs
Sparing of oculomotor, abducens, Onuf’s MN
Cognitive changes may develop
(executive function, mood)

5. ALS: A Disorder of Upper and Lower Motor Neurons
To muscle
Motor neurons in the somatosensory cortex,
brain stem and spinal cord; frontotemporal
cortex (in some patients)

6. ALS occurs in Familial and Sporadic Forms
Al-Chalabi, A. & Hardiman, O. (2013)
Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.203
SOD1
FUS
TARDP
C9ORF72

7. Challenges to Therapy
Find the crucial targets
• ALS is a syndrome with many
causes
• Variable presentation and progression
• Complex pathogenesis: Disruption
of multiple networks
• Mechanisms of disease progression
differ from onset
(neuroinflammation)
• Motor nuclei in different stages of
disease
• Not just a motor neuron disease
• Insufficient preclinical models
• Pharmacokinetics (CNS delivery)
Lymphocyte

8. Motor neurons are dysfunctional
before they die …
• Trouble receiving messages
• Trouble sending messages
• They pull back to regroup
• They abandon muscle
• Muscle wastes from inactivity
About 50% of motor neurons can be
lost before before symptoms
• Denervation – reinnervation
• Sprouting (increase in MU size)

9. Upset Gene Expression in ALS
What is RNA?
• RNA is the intermediate between
the DNA template and protein
• Messenger RNA (mRNA) is the
molecule carrying the code out of
the nucleus to be translated into
protein
• What genes get expressed depends
on the cell and its circumstances
• Every step is regulated
• microRNA is a special type of
RNA that regulates mRNA
• Many steps are affected in ALS
microRNA

10. Defects of RNA Metabolism in ALS
• Mutations in RNA binding proteins cause ALS
(FUS, TARDP, RGNEF...)
• RNA metabolism and function is impaired in
many forms of ALS including sporadic ALS
• RNA-ALS project focuses on miRNAs that
regulate mRNAs encoding proteins important
for motor neuron dendrites
– neurofilament proteins are disrupted in ALS
• Is altered expression of particular miRNAs a
key problem in motor neuron dysfunction in
ALS and can we fix it to keep neurons
connected and functional
microRNA

11. The RNA-ALS Team
Transnational consortium of investigators with expertise in
clinical neurology and pathology, RNA metabolism, motor
neuron cell biology and experimental modelling
• Heather Durham: tissue culture models of ALS;
motor neuron biology, stress responses
• Mike Strong: neurologist, biochemist, expert in
RNA biology, established tissue bank for
experimentation
• Edor Kabashi: zebrafish models of ALS, ALS
genetics, access to tissue bank
• Eran Hornstein: world expert on miRNA and its
involvement in disease including ALS

12. From the Patient to the Lab and
back to the Patient
Strong
Durham
Hornstein
Durham
Hornstein
Kabashi
Hornstein
The Goal and the Hope!
Experimental Models ALS ClinicsALS Tissue Bank
Strong

13. The Collaborative Model
• Collaborative research model: Question-driven, not
expertise-driven. Define the right questions and
assemble the team (or contracts) to answer them.
• Importance of Research Platforms (Genomics
proteomics, tissue/cell banks, databases, etc.)
• Collaborative funding model: Leverage donations to
health charities through partnerships:
– e.g., ALS Society of Canada
• E-RARE partnership
• Brain Canada partnership (Ice Bucket Challenge funds)

14. Challenges
• Having a reasonable success rate and value/effort
• Open and flexible vs prescribed and bureaucratic: striking
a balance

15. Thank you for your attention
Durham lab
Sandra Minotti
Michael Tibshirani
Benoit Gentil
Aaron Howe
Miranda Tradewell
Luan Tran
Kyle St. Louis
Tanya Gupta
Kathleen Sullivan
James Mattina
Collaborating labs
Stéphane Richard
Lawrence Hayward
Michael Strong
Edor Kabashi
Eran Hornstein
Janice Robertson
Caroline Rouaux
Luc Dupuis
Funding provided by:
ALS Canada Bernice Ramsay Discovery Grant
MDA
ALSA
E-RARE 2 (CIHR, ALS Canada, FRQS)
Proudfoot fellowship
ARSACS Foundation