Transcript Current Research Areas

ALS Research Update 2008
Richard A. Lewis MD
Director, Hiller ALS Clinic and Research Center
Wayne State University School of Medicine
Detroit, Michigan
Current Research Areas
(as shown on ALSA website)
Main Research Area
Sub Research Area
Clinical Trials
Disease Process of ALS
Axon Structure and Dynamics
Cell Death and Apoptosis
Cognitive Changes with ALS [Frontotemporal Dementia]
Glutamate
Inflammation
Mitochondria
SOD1 and ALS (copper zinc superoxide dismutase 1)
Environmental Factors
Genetics of ALS
Laboratory Models of ALS
Therapies for ALS
Cell Targets
Gene Therapy
RNA Therapy
Stem Cells
Trophic Factors
Biomarkers
Axonal Transport
Neurofilaments are proteins that
maintain axonal structure. Defects
cause motor neuron disorders
Mutations in Tubulins, Dynein
and Dynactin, all involved in axonal
transport, have been shown to cause
motor neuron disease
Neuromuscular Junction Shows
Early Pathology in ALS
NMJ is the connection between the
nerve and the muscle. The site of
attack in Myasthenia Gravis.
In ALS the NMJ appears to degenerate
before the motor neuron degenerates.
This suggests that there is loss of the
nutrients and energy to this structure.
Dr. Loeb’s laboratory at WSU is looking
at Neuregulin, a protein important to the
development of both the NMJ and
Motor Neuron
Mitochondria
• The energy factories of all cells
• Motor neurons have very high energy
demands
• SOD1 important to mitochondrial function
• Early changes in mitochondria may cause
motor neuron death
Mitochondrial Transport
• Mitochondrial transport is important in
providing energy throughout the motor nerve.
• Techniques now available to study transport
• Dr. Jun Li at WSU is currently looking at
transport of mitochondria and other structures
in new genetic forms of MND
ALS and Frontotemporal Dementia
• Impulsive, emotional behavior without
memory disturbance
• 70% of patients with ALS may have FTD
• TDP-43, effects mRNA in constructing
neurofilaments
• May be common thread between ALS
and FTD
Genes associated with Motor
Neuron disease
• TDP-43 (TAR DNA binding protein 43) in one family and
2 other sporadic ALS
• ALS2 Alsin (Juvenile Primary Lateral Sclerosis)
• NEFH(a small number of cases),
• ALS4 Senataxin (Juvenile ALS)
• Vesicle associated protein B- Brazil with autonomic.
• FIG 4 (WSU/U of M)- also Schwann Cell
• Dynactin- vocal cord paralysis and distal weakness
• Heat Shock Protein 22
• Heat Shock Protein 27
• GARS- Glycine tRNA synthetase
Biomarkers
• A way of tracking the progression of a
disease and monitoring the effect of a
treatment
• Serum or Spinal fluid substance
• Neuroimaging
• Physiologic parameters- MUNE
Treatment
Cell Targets
• Astrocytes
– Supply trophic factors to motor
neurons
• Microglia
– Inflammatory cells
• Oligodendrocytes
– Produce CNS myelin
The spread of disease may be prevented by targeting
treatments to these cells
Gene Therapy
• Using viruses and other vectors which
can invade cells, researchers can
introduce new genes, trophic factors
and other substrates into neurons or
glia.
RNA Interference and Anti-Sense Therapy
• Anti-sense molecules can attach to RNA
and prevent protein formation
• Short RNAi placed in cells will induce the
cell to destroy the corresponding gene
• SOD mutations produce an abnormal
protein
• RNAi could be targeted to the mutant SOD
gene to prevent the production of the
protein
• A potentially powerful tool for a number of
diseases
Stem Cells- Some Reasons to be
Encouraged
•
Ann Neurol. 2006;60:32-44.
Recovery from paralysis in adult
rats using embryonic stem cells.
– Combination of motor neurons from embryonic stem cells,
neurotrophic factor to promote axonal growth and other factors
produced functioning motor neurons innervating muscle
•
Nov 22, 2007
Hadassah uses stem cells for MS, ALS
patients
• Injected stem cells into spinal cords obtained from the
patient’s own bone marrow
– Single injection
• “Conditions improved or stabilized” but unclear if
significant
Stem Cells- Reasons to be Cautious
• Rats aren’t humans- our nerves have to grow a
long way
• Will replacing cells stop the disease or will these
cells get sick also?
• How do we get cells to all the places they need
to go?
• Can stem cells replace astrocytes, Renshaw
Cells and other supportive cells that don’t
require long axons to grow?
Lithium
• Report in February 2008 shows improved
outcomes in SOD1 mice and in people
with ALS.
• Mood stabilizer used for over 30 years for
Bipolar Disorders.
• Shown to be neuroprotective in brain
ischemia and neurodegeneration models
Lithium prolongs life and delays
onset of disease in SOD-1 Mice
• Mean survival increased by 36% (110 to 148
days)
• Increased disease duration from 9 to 38 days
• Delayed onset of paralysis
Lithium Improves Motor Neuron
Survival
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Size of Motor Neuron
Number of Neurons
Reduced astrocytosis
Decreased ubiquitin
Decreased SOD1 aggregation
Increase in Renshaw cells with beneficial
effects on motor neurons
• Increase in healthy mitochodria
Lithium Improves Function and
Survival of ALS Patients
• Very small study
– 16 on Li++ + Rilutek and 28 on Rilutek
• 15 month follow-up
– 100% alive on Li++ vs 71% on Rilutek alone
– FVC decrease of 15% on Li++ vs 30%
– ALSFRS-R decrease of 5 on Li++ vs 16 points
– MRC (strength) decrease of 18% on Li++ vs
35% on Rilutek alone
Clinical Trials
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Compound or Trial
Quality of Life Survey
• Memantine Therapy
Arimoclomal Trial for Familial ALS
• Tamoxifen
Thalidomide (modulate cytokines)
New Gene Study
• Ceftriaxone
• Diaphragm Training
Other Clinical Trials
• Memantine (Alzheimer’s drug that contols Ca++ influx into cells)
• + Pramipexole (+stereoisomer of Mirapex used for
Parkinson’s allows larger doses for neuroprotection)
• Edavarone (free radical scavenger cleans up waste )
• Sodium Valproate (Histone deacetylase inhibitor modulates
gene expression)
• Glatiramer Acetate (Immunomodulating MS drug)
• Arimoclomol (Improves molecular chaperone function needed
in cellular stress)
• Atorvastatin (Lipitor) (Anit-inflammatory and neuroprotection)
Diaphragmatic Pacing
• Surgical implantation of electrodes on the
diaphragm
• Stimulation improves breathing in spinal
cord injury
• Prelim studies in ALS at Cleveland Clinic
encouraging
• But……..
Thanks for Your
Attention!