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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). Axonal Transport . Neurofilaments are proteins that

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als research update 2008

ALS Research Update 2008

Richard A. Lewis MD

Director, Hiller ALS Clinic and Research Center

Wayne State University School of Medicine

Detroit, Michigan

axonal transport
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
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

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

Mitochondrial Transport
als and frontotemporal dementia
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
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

A way of tracking the progression of a disease and monitoring the effect of a treatment

Serum or Spinal fluid substance


Physiologic parameters- MUNE

treatment cell targets
TreatmentCell Targets

The spread of disease may be prevented by targeting treatments to these cells

  • Astrocytes
    • Supply trophic factors to motor neurons
  • Microglia
    • Inflammatory cells
  • Oligodendrocytes
    • Produce CNS myelin
gene therapy
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
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
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, 2007Hadassah 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
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?
  • 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
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
Lithium Improves Motor Neuron Survival
  • 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
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
Clinical Trials

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
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
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……..