1. ALS Research Update 2008 Richard A. Lewis MD Director, Hiller ALS Clinic and Research Center Wayne State University School of Medicine Detroit, Michigan

2. Main Research Area Sub Research Area Clinical Trials Disease Process of ALSAxon 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 ALSCell Targets Gene Therapy RNA Therapy Stem Cells Trophic Factors Biomarkers Current Research Areas (as shown on ALSA website)

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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.

12. 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

13. 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

14. 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?

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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)

21. 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……..

22. Thanks for Your Attention!