research programs in light of ice bucket challenge
TRANSCRIPT
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Research programs in light of ICE BUCKET CHALLENGE
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Presentation Overview
• The ALS Association Research Programs
• Opportunities and Challenges for Therapy Development in ALS
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Research Program Strategies
• Establishment of a translational program TREAT ALS™
• Fund academic-industry partnerships
• Provide infra-structure for multi-center clinical trials
• Consortium initiatives and Global research
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The ALS Association Research Institute
Public PolicyALS Clinical Centers
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Key Focus Areas in ALS Research• Genetics
• Understanding Disease Mechanisms-disease modeling
• Therapeutic Development
• Stem Cells for therapy and drug discovery
• Clinical Studies-clinical trials and clinical management
• Biomarkers
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Aging
Genes Environment
SOD1
GenderRis
k
Low
Hig
h
smoking
Ris
k
Age
Youth
Ris
k
Gene-Environment Interactions and Aging
5-10% familial
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ALS genes timeline
1990 1995 2000 2005 2010
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1990 1995 2000 2005 2010
ALS genes timeline
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Familial ALS
SOD1
FUS/TLS TDP-43
C9ORF72
?
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0
5
10
15
20
25
30
19931994
19951996
19971998
19992000
20012002
20032004
20052006
20072008
20092010
20112012
2013
SOD1
senataxinVAPBalsin
dynactin
TDP43NTE
ANG
OPTND-AAVCPAtxn2
FUSPON1-3KIFAP3ELP3CHGBUNC13A
C9orf72TAF15ubqIn2p62sigR-1EphA4
hnRNPA2B1 hnRNPA1
Pfn1
Each gene defines pathways and treatment targets.
The rate of gene discovery in ALS is increasing:>25 ALS genes
# o
f G
en
es
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First Four Initiatives
• New York Genome Center
• Project Mine
• Neurocollaborative
• ALS ACT (Accelerated Therapeutics)
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// Confidential ©2014
dedicated to applying
genetics, genomics and
bioinformatics to the study
of neurodegenerative
diseases, including ALS.
NEW YORK GENOME CENTER & ALS
RESEARCH
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Neurocollaborative
• Don Cleveland UCSD
• Steve Finkbeiner UCSF
• Clive Svendsen Cedar Sinai
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Innovative Approaches for Treatment and Drug Development
• Antisense Oligonucleotides
• Stem Cell Therapy
• Gene therapy
• Induced pluripotent stem cells for screening new compounds
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5’’
Endogenous RNase H mediated degradation of the mRNA in a DNA/RNA duplex
G37R G93C G93CG37R
G85R
H48Q H48Q
H46R
Zn++
Cu++A4V
I113T
Zn++
ALSA-initiated Study 2003
Antisense Approach to Lower SOD1
Cleveland, Miller, Smith
Collaboration with ISIS
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Antisense Drugs Target RNA, not Proteins
Gene mRNA
Transcription
No Translation of
Disease-Causing
Protein
NO DISEASE
ANTISENSE DRUGS (Oligonucleotides)
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Repeat Primed PCR
Expanded
Southern:
Up to 1500 repeats
C9orf72 gene
Normal
(GGGGCC)n
C9orf72 gene
Modified from DeJesus-Hernandez Neuron (2011)
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Intrathecal injection of AAV9 and AAVrh10 leads to transgene expression in the entire spinal cord and brainstem
Zuoshang Xu
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Intraventricular injection of AAV9 and AAVrh10 leads to widespread transduction in the forebrain including the motor cortex
Zuoshang Xu
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102-103 improved sensitivity Phenotypic screens Z’ > 0.8
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Automated Microscopy: A Powerful Tool for Unraveling Cause and
Effect Relationships and Doing Clinical Trials in a Dish
Steve Finkbeiner
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Generation of Induced Pluripotent Stem
(iPS) Cell Lines From Human Skin Cells
Human Skin Biopsy
yes
Dr. Shinya Yamanaka’s
Technology (2012 Nobel Prize)
Stem CellsSkin Cells
Motor Neurons
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ALS Association/Cedar Sinai Stem Cell Core
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ALS ACT (Accelerated Therapeutics)• Partnership with MGH, General Electric
and a Foundation
• Biomarker Development
• Therapeutic Development
• Neurobank-central to all four initiatives
• GUID
• Phase II A Pilot Studies
• Innovative call for novel ideas and biomarkers
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TREAT ALS™NEALS Clinical Network leads to
increased trials for ALS
0
2
4
6
8
10
12
14
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
# of
tria
ls
Combination Funding
Foundation
Government
Industry
TREAT ALS
Funding
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ALS ACT Clinical Pilot Studies RFA
• Released 22 October 2014
• Solicit letters of intent for phase II A clinical studies with a strong biomarker plan
• Proposals with additional funding partners will be favourably reviewed
• Open to academia and industry
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Urgent Need for Biomarkers• Improved Diagnosis
• Stratification in clinical trials
• Improved Clinical Trials-outcome measures;
• pharmocodynamic marker for target engagement
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• Plasma, Serum, CSF, DNA– > 15,000 cryovials of plasma– ~ 1300 cryovials of serum– ~ 5000 cryovials of CSF– > 300 DNA samples
Request Sample Access: Tara Lincoln ([email protected])
Baseline Plasma
6mo Plasma
12mo Plasma
18mo Plasma
CSF DNA
Early ALS 200 124 76 40 98 116
UMN/LMN
49 28 12 9 24 39
Mimics 98 - - - 43 69
Healthy 102 - - - 52 52
NEALS Biorepository
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Identification of dysregulated microRNA signature in blood monocytes and spinal cord from ALS subjects
Blood monocytes Spinal cord
J Clin Invest. 2012
Spinal cordBlood monocytes
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EAAT2 Rat PET Imaging: WT vs. ALS Model
Frontal Cortex (FrCTx)
Caudate/Putamen (CP)
Lumbar spine
coronal
Cerebellum (CE)
Motor nuclei (MNuc)
FrCTx
Thalamus (TH)
Fr & Cing
CTx
TH
Decreasing spine
signal In ALS
rat model
0.25SUV
5.0SUV
Sprague-Dawley rat
0.50 mCi of tracer
15 min post injection
sagittal
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ALS diagnostic: Ratio of pNFH to complement C3 Levels
A cut-off value was obtained that was 90% accurate for ALS in 106 subjects in a retrospective study.
J Neurochem 117: 528-537 (2011)
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Plasma pNF-H levels in 19 ALS and 19 Control patients over 4 months
ALS Patients
0.00
0.50
1.00
1.50
2.00
2.50
3.00
Baseline Month 1 Month 2 Month 3 Month 4
Pla
sma
pN
F-H
(n
g/m
l)
Control Subjects
0.00
0.50
1.00
1.50
2.00
2.50
3.00
Baseline Month 1 Month 2 Month 3 Month 4
Pla
sma
pN
F-H
(n
g/m
l)
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Seward Rutkove
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Quantitative Isometric Strength Testing
• Fixed, wireless
load cell
• No position changes or
stabilization required
ATLIS™
Accurate Test of Limb
Isometric Strength
Strain gauge
HHD
Disclosure: MGH holds a patent on this device. PL Andres is named inventor.
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What Next ?• Partnership with Jax Laboratories for
mouse model development
• Drug Discovery Contracts
• Clinical Research Studies
• Continued support of investigator-initiated research and the Milton Safenowitz Fellowship Program
• Strategic Calls for proposals
• Focus on Biomarker Development and standardization
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TARGET
IDENTIFICATION
EARLY
DISCOVERY
VALIDATED
TARGETS
THERAPEUTIC
DEVELOPMENT
PRE-CLINICAL
STUDIES
CLINICAL
TRIALS
TREAT ALS PROGRAM
GLOBAL BIOMEDICAL RESEARCH
CLINICAL
MANAGEMENT
TOOLS
MODEL
SYSTEMSBIOMARKERS
Laboratory bedside
SOD1 antisense trial-UCSD/Isis Pharmaceuticals
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Model Systems to Understand Disease Mechanisms
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Ilieva et al, J. Cell Biol., 2009 40
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Cat Lutz, Ph.D.Director, Mouse ResourcesDirector, Rare and Orphan Disease Center The Jackson Laboratory
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Improving the Drug Discovery Pipeline
42
50% 30%10% 30%>90% failure in phase IIB
Better, Faster, Stronger
• Design• Phenotypic validity• Translational power• Therapeutic platform• Time
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Challenge:
Can technological innovation lead
us to process innovation?
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Genetic Engineering Technologies at JAX
Tim
eli
ne:
8 W
ee
ks
Milestone 3
Founder Identification
Milestone 1
Guide Design,
Synthesis & Testing
Milestone 2
Founder Generation
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MOUSE MODEL RFA
• Request ideas for priority models to be developed
• Jax labs develops models
• The ALS Association owns models-no MTA blocking or delaying access to industry and other academic institutions
• Open Source availability of models for investigator community globally
• Two initial models already in planning to set up partnership 45
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Challenges for Drug Discovery
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Public-Private Partnerships
Fishburn 2012
NGO’sThe ALSAssociation
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Industry and Biotech focused on ALS
• Biogen Idec Synapse
• Bristol Myers Squibb Avanir
• Pfizer Amorfix
• Genzyme/Sanofi Aventis ALS Biopharma
• Genentech/Roche Santhera
• Cytokinetics UBC
• Neuraltus Biofocus
• Neuralstem Osainix
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Milton-Safenowitz Post-Doctoral Fellowships