1 / 11

Immunomodulatory therapy for parkinson’s disease

Eric Zanelli, PhD Bethesda, March 5, 2010. Induction of an anti-inflammatory immune response toward toxic species of alpha-synuclein. Immunomodulatory therapy for parkinson’s disease. Parkinson’s Disease.

ganya
Download Presentation

Immunomodulatory therapy for parkinson’s disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Eric Zanelli, PhD Bethesda, March 5, 2010 Induction of an anti-inflammatory immune response toward toxic species of alpha-synuclein Immunomodulatory therapy for parkinson’s disease

  2. Parkinson’s Disease • Parkinson’s disease (PD) is a neurodegenerative disease with loss of dopamine-containing neurons in the substantianigra • Suggested causes of PD include: • Mitochondrial dysfunction • Oxidative stress • Impaired protein degradation processes (misfoldeda-synuclein) • Additionally, immune system involvement is established (either primary or secondary) • Innate immunity • Adaptive immunity • PD patients would benefit from an immunotherapy that • Clears toxic oligomers and protofibrils through a-syn-specific antibodies • Induces monocytes/microglia with anti-inflammatory phenotype

  3. Immunomodulatory Approach for PD • Target Product Profile: • First-line disease modifying treatment • Weekly or bi-weekly subcutaneous administration in a pre-filled syringe/auto-injector • Exhibit excellent long-term safety and tolerability profile enjoyed by marketed copolymers such as Copaxone™ (Teva) • Dual Mechanisms of Action: • Induces antibody-mediated clearance of post-translationally modified, toxic alpha-synuclein oligomers and protofibrils found in PD patients • Induces an immunoregulatory, neuroprotective immune response capable of dampening inflammatory microenvironments found in PD patients

  4. Amino Acid Copolymer PlatformDEEP: Directed Expansion of Epitope Permutations • What is an amino acid copolymer? • A single manufacturing peptide entity comprising multiple related antigenic determinants • Promiscuous MHC class II binding • Enhanced immunogenicity Immune Modulating Copolymer • Broad Application • Therapeutic vaccines for various disorders • Prophylactic vaccines against highly mutating infectious agents • Ligands for antibody screening Epitope specific copolymer Specific Antigenic Determinant

  5. Immune System Involvement in Parkinson’s Disease In Mouse In Man CD4+ and CD8+ T cells ten-fold increase in substantia nigra in PD patients as compared to age-matched controls, Brochard et al, J Clin Invest (2009) 119:182 Pro-inflammatory markers Increased production of MCP-1, IL-8, IFNg, TNFa by PBMCs from PD patients, Reale et al, Brain Behav Immun (2009) 23:55 • Th17 cells • promote neurodegeneration in MPTP model, Reynolds et al, J Immunol (2010) 184:2261 • Vasoactive Intestinal peptide (VIP) • induces Treg which attenuate microglia-mediated inflammation, Reynolds et al, J Immunol (2010) 184:2261 • FasL+ CD4+ T cells • contribute to neurodegeneration in MPTP model, Brochard et al, J Clin Invest (2009) 119:182

  6. The Copaxone/PI-2301 Experience Copaxone™ PI-2301 Phase II in RR-MS initiated 52-amino acid-long peptides made of Y, F, A and K Improved MHC class II binding Induction of anti-inflammatory response in man demonstrated Better preclinical efficacy Better effect on monocytes Improved bioavailability (N-terminal acetylation) • Approved by FDA in 1996 for treatment of RR-MS • 20-200 amino acid long peptides made of Y, E, A and K • Limited effect on monocytes • Induces regulatory T-cell response • Limited bioavailability • Suspected neuroprotective effect?

  7. Copaxone in Animal Models of Neurodegeneration • Copaxone-specific T-cells protect mice from MPTP toxicity Benner et al, Proc Natl Acad Sci USA (2004) 101:9435 • Effect results in markedly decreased activation of microglia • Increased expression of Glial cell-Derived Neutrophic Factor (GDNF) might play a role • Copaxone vaccination reduces b amyloid accumulation in APP/PS1 transgenic mice Butovsky et al, Proc Natl Acad Sci USA (2006) 103:11784 • Induction of phenotype switch in microglia • Increased production of Insulin-like Growth Factor-1 (IGF-1) by microglia

  8. Decreased Production of pro-inflammatory Cytokines by Macrophages cultured with PI-2301

  9. Immune Response alone will not work • Concept of vaccine therapy for neurodegenerative diseases is currently tested in man • Anti-bamyloid (Ab) trials through either active or passive immunization in Alzheimer • 6% of Alzheimer’s patients treated with AN1792 in Phase IIa (study 201) developed meningoencephalitis, Pride et al, NeurodegenerDis (2008) 5:194 • T-cell response to Ab peptide was characterized as Th1 in contrast to Th2 response observed in study 102 • Changes in formulation? • Antibody responses in both studies were similar • Use of adjuvant QS-21 probably promoted the Th1 response • Importance of maintaining the correct Th2 response as induced by Copaxone or PI-2301

  10. Proposed Design for a-syn Amino Acid Copolymer Tri-nitrations DNEAYEMPSEEGYQDYE Target Region: a-syn 121-137 Species Alterations Phosphorylation • Immune response targeted at a 17-amino acid region, • Specificity for toxic species guaranteed through use of phosphorylated Ser (S) and nitrated Tyr (Y), • Substitutions incorporated to account for interspecies variabilities, • Immunogenicity guaranteed by % Ala (A) incorporation at every position and compound length through tandem-repeats of the same region, • Tyr (Y) and Glu (A) also found in Copaxone provide anchoring residues to various MHC class II molecules and T-cell help, • Goal is to induce specific immune response to toxic species of a-syn, only • without need for strong adjuvant, • while preserving anti-inflammatory properties found in Copaxone and PI-2301.

  11. A testable hypothesis a-synuclein amino acid copolymer induces: • In vitro • An expansion of anti-inflammatory monocytes and/or T-cells with regulatory properties, • Antibodies capable of clearing misfolded protein deposits. • ASO Mice • A reduction in alpha-synuclein burden, • Specific effects on motor and olfactory measurements in ASO mice, • Alterations in striata and ventral midbrain. • MPTP-induced Toxicity • Protection of nigrostriatal pathway. From: SH Appel, J Clin Invest (2009) 119:13

More Related