ALS Research Update 2008

Richard A. Lewis MDDirector, Hiller ALS Clinic and Research Center

Wayne State University School of MedicineDetroit, Michigan

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

Current Research Areas(as shown on ALSA website)

Axonal Transport

Neurofilaments are proteins that maintain axonal structure. Defects cause motor neuron disorders

Mutations in Tubulins, Dyneinand 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 degeneratebefore the motor neuron degenerates.This suggests that there is loss of thenutrients and energy to this structure.

Dr. Loeb’s laboratory at WSU is looking at Neuregulin, a protein important to thedevelopment 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

TreatmentCell 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

• 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

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!