wilson arf webinar presentation
DESCRIPTION
Edward Wilson presentation made at the Alzheimer Research Forum webinar held November 7, 2012 (www.alzforum.org)TRANSCRIPT
A novel, combinatory passive immunotherapy for AD treatment in the McGill AD rat model
Presented by Edward WilsonDoctoral Candidate, Integrated Program in Neuroscience,
McGill University
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
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
Aim 1: Does an antibody to neuroserpin 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
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
Aim 2: Does a tandem treatment with neuroserpin 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
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
Aim 3: Is a tandem treatment with neuroserpin 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
Aim 3: Is a tandem treatment with neuroserpin 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
Passive immunization
• Promising clinical trials
• No immune response is required
• Treatment can be easily discontinued
• Specific targeting