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The ALS Association Research Where are the gaps and Opportunities
Presentation Overview
• Brief overview of ALS
• Opportunities and Challenges for Therapy Development
Aging
Genes Environment
? APOE
SOD1
GenderRis
k
Low
Hig
h ? retrovirus
? pesticides
smoking
high glut diet
Ris
k
Age
Youth
Ris
k
Gene-Environment Interactions and Aging
5-10% familial
G37R G93C G93CG37R
G85R
H48Q H48Q
H46R
Zn++
Cu++A4V
I113T
Zn++
> 100
different
mutations
known
Mutant- Copper/Zinc SOD1 mediated Toxicity (include genetics summary slide)
The ALS Association Research Department
Model Systems for ALS drug discovery
Ilieva et al, J. Cell Biol., 2009 6
Jeff Lichtman
Involvement of astrocytes, microglia and muscle
Familial ALS
C9orf72
SOD1
FUS TDP43
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
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
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
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
Public-Private Partnerships
Fishburn 2012
NGO’sThe ALSAssociation
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
• Intrathecal drug administration – Lumbar Puncture bolus injection
• ASOs have long half-lives (several months) in CNS tissue, with even longer duration of action, so enables infrequent dosing
• For more frequent dosing, there are implantable devices that can also be used
Intrathecal ASO Drug Delivery to the CNS
IHC against drug in monkey spinal cord following intrathecal delivery of ASOneedle
15 Courtesy of Frank Bennett, ISIS
Repeat Primed PCR
Expanded
Southern:
Up to 1500 repeats
C9orf72 gene
Normal
(GGGGCC)n
C9orf72 gene
Modified from DeJesus-Hernandez Neuron (2011)
Intrathecal injection of AAV9 and AAVrh10 leads to transgene
expression in the entire spinal cord and brainstem
Intraventricular injection of AAV9 and AAVrh10 leads to
widespread transduction in the forebrain including the motor cortex
TREAT™ ALS/NEALS Clinical Network
…the ALS pipeline has many treatments in development for ALS
• Phase II
– Tirasemtiv (CK-2017357)– Immunosuppression (4) – Gilenya– Mexiletine– Nuedexta– Ursodiol– NurOwn™ – Neuralstem– NP001– GSK1223249– High fat nutrition– Exercise– Tamoxifen/Creatine– Diaphragm pacing– GM604
• FALS SOD1– ISIS333611– Arimoclomol
• FALS/SALS – C90rf72
www.clinicaltrials.gov
www.alsconsortium.org
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)
Cervical Cord Magnetic Resonance Spectroscopy in ALS
Michael Benatar
Charlie Stagg
Charlie Stagg
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
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
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
Use of Patient-Specific iPS Cells to Investigate Pathogenic Mechanisms of GGGGCC Repeats in C9ORF72
-- GGGGCC repeat expansion is the most common genetic mutation in ALS
-- We have generated multiple iPS cell lines from 3 patients with GGGGCC repeats
-- We found RNA foci in iPSC-derived cortical neurons and motor neurons
-- We are investigating how to reduce repeat toxicity in human motor neurons
Control Patient
Fen-Biao Gao
Automated Microscopy: A Powerful Tool for Unraveling Cause and
Effect Relationships and Doing Clinical Trials in a Dish
Steve Finkbeiner
102-103 improved sensitivity Phenotypic screens Z’ > 0.8
Provided by Gendron T. and Petrucelli L.Unpublished observation
Detection of RAN products in iPS cell culture supernatants
RAN products may be released into supernatants and could therefore be used a alternative biomarker readout
The ALS Association Opportunities• Centralize and co-ordinate consortium
efforts
• Pursue the most promising targets and therapeutic approaches and partner with industry to bring to the clinic
• Innovative academic-industry pre-competitive partnerships-especially biomarkers
• Exploit technologies both for people living with the disease now and future therapies
• Large Data initiatives-Project MINE
• Phase II clinical trials
Milton-Safenowitz Post-Doctoral Fellowships