Wilson arf webinar presentation

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Edward Wilson presentation made at the Alzheimer Research Forum webinar held November 7, 2012 (www.alzforum.org)

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Wilson arf webinar presentation

  1. 1. A novel, combinatory passiveimmunotherapy for AD treatment in the McGill AD rat model Presented by Edward Wilson Doctoral Candidate, Integrated Program in Neuroscience, McGill University
  2. 2. Immunotherapy trials in humans• Bapineuzumab Phase III (Janssen/Pfizer) i.v. discontinued• Solanezumab Phase III (Eli Lilly)• MABT5102A Phase II (Genentech/AC Immune)• Gantenerumab Phase II (Hoffmann-LaRoche)• GSK933776 Phase II (GSK) discontinued• Ponezumab Phase II (Pfizer/Rhinat) discontinued• BAN2401 Phase I (Esai/BioArtic)• Gammagard 10% IGIV Phase III (Baxter HC)• Octagam 10% IVIG Phase II (OctaPharma) completed• NewGam 10% IVIG Phase II (Sutter Health) Adapted from Cindy Lemere
  3. 3. Solanezumab• humanized monoclonal antibody• binds to the central region of β-amyloid and helps to remove it before plaque formation• i.v. treatment for mild-to-moderate AD patients• Acute treatment of tg mice attenuated or reversed memory deficits No cognitive improvement in patients with fully established disease
  4. 4. Evoking the plasmin cascadeBruno and Cuello,Proc Natl Acad Sci 2006 Directly degrades Aβ
  5. 5. Leon et al,J Alz Disease 2010
  6. 6. Aim 1: Does an antibody toneuroserpin produce beneficial effects in an AD rat model?• Hypothesis: Decreasing neuroserpin levels in the aged McGill rat AD model will lead to increases in 1) NGF, 2) decreased amyloid pathology, and 3) improved memory performance
  7. 7. Aim 1: Does an antibody to neuroserpin produce beneficial effects in an AD rat model?• Experimental strategies: – Passive immunization of 13 month old McGill rats with anti- neuroserpin antibody at high, low, and intermediate doses by IP injection every week – Behavior – Morris Water Maze, novel object recognition and object location task – Protein analysis (Western blot) – levels of tPA, plasmin, pro-NGF, NGF, BDNF, synaptic proteins – Histology – synaptic density, amyloid pathology – ELISA analysis – soluble and insoluble Aβ species – Zymography – activity of tPA and plasmin• Expectations: – Increased activation of plasmin will increase Aβ clearance – Increased NGF and decreased pro-NGF will increase synaptic boutons of cholinergic neurons – Increased cognitive performance
  8. 8. Aim 2: Does a tandem treatment withneuroserpin and Aβ-specific antibodies have synergistic effects?• Hypothesis: Decreasing neuroserpin levels in aged McGill rats in conjunction with stimulating clearance of Aβ will have a greater effect on 1) amyloid pathology and 2) cognitive performance than modulating neuroserpin alone
  9. 9. Aim 2: Does a tandem treatment with neuroserpin and Aβ-specific antibodies have synergistic effects?• Experimental strategies: – Passive immunization of 13 month old McGill rats with Solanezumab and neuroserpin antibody at low, intermediate, and high doses at 13 months of age by IP injection every week – Behavior – Morris Water Maze, novel object recognition and object location task – Protein analysis (Western blot) – levels of tPA, plasmin, pro-NGF, NGF, BDNF, synaptic proteins – Histology – synaptic density, amyloid pathology – ELISA analysis – soluble and insoluble Aβ species – Zymography – activity of tPA and plasmin• Expectations: – Aβ clearance will be more efficient than with the neuroserpin antibody alone – Increased NGF and decreased pro-NGF will increase synaptic boutons of cholinergic neurons – Cognitive performance will be improved over Aim 1 due to increased NGF and increased removal of Aβ
  10. 10. Aim 3: Is a tandem treatment withneuroserpin and Aβ-specific antibodies able to prevent AD pathology?• Hypothesis: Treating adult McGill rats with anti-neuroserpin and anti-Aβ before plaque deposition stage will 1) prevent the development of amyloid pathology and 2) improve early behavioral deficits
  11. 11. Aim 3: Is a tandem treatment withneuroserpin and Aβ-specific antibodies able to prevent AD pathology?• Experimental strategies: – Passive immunization of McGill rats with Solanezumab and neuroserpin antibody beginning at 3 months of age by IP injection every week – Analyze at 6 months of age – Behavior – Morris Water Maze, novel object recognition and object location task – Protein analysis (Western blot) – levels of tPA, plasmin, pro-NGF, NGF, BDNF, synaptic proteins – Histology – synaptic density, amyloid pathology – ELISA analysis – soluble and insoluble Aβ species – Zymography – activity of tPA and plasmin• Expectations: – Early clearance of Aβ will prevent amyloid pathology – Increased NGF and decreased pro-NGF will increase synaptic boutons of cholinergic neurons – Early cognitive defects will be reversed
  12. 12. Passive immunization • Promising clinical trials • No immune response is required• Treatment can be easily discontinued • Specific targeting
  13. 13. Thank YouGroup members: Rebecca Skerrett, Tatiana Cerneira, Paulina Davis, Sarah Hescham

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