Active immunization therapies for Parkinson's disease and multiple system atrophy
Corresponding Author
Achim Schneeberger MD
AFFiRiS AG, Vienna, Austria
Correspondence to: Dr. Achim Schneeberger, AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, Austria1030, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Achim Schneeberger MD
AFFiRiS AG, Vienna, Austria
Correspondence to: Dr. Achim Schneeberger, AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, Austria1030, E-mail: [email protected]Search for more papers by this author[Correction added on 21 September 2015, after first online publication: article title changed per editor request]
Funding agencies: This work was supported by grants from the Michael J Fox Foundation and the European Union Seventh Framework Program (FP7/2007-2013) project SYMPATH (grant agreement: 602999).
Relevant conflicts of interest/financial disclosures: A.S., M.M., and L.T. are employees of AFFiRiS, the company that commercializes the AFFITOPE® technology described in the manuscript.
Full financial disclosures and author roles may be found in the online version of this article.
Abstract
Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs. © 2015 International Parkinson and Movement Disorder Society
References
- 1Galvin JE, Lee VM, Trojanowski JQ. Synucleinopathies: clinical and pathological implications. Arch Neurol 2001; 58: 186–190.
- 2Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997; 388: 839–840.
- 3Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci 2004; 24: 6715–6723.
- 4Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 2000; 20: 3214–3220.
- 5Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromolecular Med 2003; 4: 21–36.
- 6Lansbury PT, Jr., Brice A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr Opin Cell Biol 2002; 14: 653–660.
- 7Lindström V, Ihse E, Fagerqvist T, et al. Immunotherapy targeting α-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders. Immunotherapy 2014; 6: 141–153.
- 8Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 2004; 127: 2657–2671.
- 9Al-Chalabi A, Durr A, Wood NW, et al. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS One 2009; 4: e7114.
- 10Shults CW, Rockenstein E, Crews L, et al. Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 2005; 25: 10689–10699.
- 11Yazawa I, Giasson BI, Sasaki R, et al. Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 2005; 45: 847–859.
- 12Olanow CW, Brundin P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov Disord 2013; 28: 31–40.
- 13Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24: 197–211.
- 14Luk KC, Kehm V, Carroll J, et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012; 338: 949–953.
- 15Watts JC, Giles K, Oehler A, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A 2013; 110: 19555–19560.
- 16Recasens A, Dehay B, Bove J, et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014; 75: 351–362.
- 17Danzer KM, Kranich LR, Ruf WP, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 2012; 7: 42.
- 18Lee HJ, Baek SM, Ho DH, Suk JE, Cho ED, Lee SJ. Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers. Exp Mol Med 2011; 43: 216–222.
- 19Angot E, Steiner JA, Lema Tome CM, et al. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 2012; 7: e39465.
- 20Lee SJ, Desplats P, Lee HJ, Spencer B, Masliah E. Cell-to-cell transmission of alpha-synuclein aggregates. Methods Mol Biol 2012; 849: 347–359.
- 21Valera E, Masliah E. Immunotherapy for neurodegenerative diseases: focus on alpha-synucleinopathies. Pharmacol Ther 2013; 138: 311–322.
- 22Stanimirovic D, Kemmerich K. Conquering the barriers: are antibody therapeutics feasible for CNS indications? Future Neurol 2015; 10: 67–70.
- 23Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64: 1553–1562.
- 24Muhs A, Hickman DT, Pihlgren M, et al. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A 2007; 104: 9810–9815.
- 25Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME(R) technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin 2010; 6: 948–952.
- 26Wang CY, Finstad CL, Walfield AM, et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer's disease. Vaccine 2007; 25: 3041–3052.
- 27Wiessner C, Wiederhold KH, Tissot AC, et al. The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci 2011; 31: 9323–9331.
- 28Masliah E, Rockenstein E, Adame A, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron 2005; 46: 857–868.
- 29Menendez-Gonzalez M, Perez-Pinera P, Martinez-Rivera M, Muniz AL, Vega JA. Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials. Curr Pharm Des 2011; 17: 508–520.
- 30Wilcock DM, Colton CA. Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers Dis 2008; 15: 555–569.
- 31Ghochikyan A, Petrushina I, Davtyan H, et al. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human alpha-synuclein: feasibility study. Neurosci Lett 2014; 560: 86–91.
- 32Winblad B, Andreasen N, Minthon L, et al. Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012; 11: 597–604.
- 33Shimamura M, Sato N, Morishita R. Experimental and clinical application of plasmid DNA in the field of central nervous diseases. Curr Gene Ther 2011; 11: 491–500.
- 34Yurek DM, Flectcher AM, Kowalczyk TH, Padegimas L, Cooper MJ. Compacted DNA nanoparticle gene transfer of GDNF to the rat striatum enhances the survival of grafted fetal dopamine neurons. Cell Transplant 2009; 18: 1183–1196.
- 35Koike H, Ishida A, Shimamura M, et al. Prevention of onset of Parkinson's disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson's disease. Gene Ther 2006; 13: 1639–1644.
- 36Chen Z, Yang Y, Yang X, et al. Immune effects of optimized DNA vaccine and protective effects in a MPTP model of Parkinson's disease. Neurol Sci 2013; 34: 1559–1570.
- 37Pizzurro GA, Barrio MM. Dendritic cell-based vaccine efficacy: aiming for hot spots. Front Immunol 2015; 6: 91.
- 38Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res 2013; 119: 421–475.
- 39Ugen KE, Lin X, Bai G, et al. Evaluation of an alpha synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease. Hum Vaccin Immunother 2015; 11: 922–930.
- 40Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 2014; 27: 1–7.
- 41Benner EJ, Banerjee R, Reynolds AD, et al. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 2008; 3: e1376.
- 42Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 2010; 184: 2261–2271.
- 43Sanchez-Guajardo V, Barnum CJ, Tansey MG, Romero-Ramos M. Neuroimmunological processes in Parkinson's disease and their relation to alpha-synuclein: microglia as the referee between neuronal processes and peripheral immunity. ASN Neuro 2013; 5: 113–139.
- 44Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature 2011; 475: 324–332.
- 45Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2002; 2: 185–194.
- 46Murshid A, Gong J, Calderwood SK. The role of heat shock proteins in antigen cross presentation. Front Immunol 2012; 3: 63.
- 47Koller MF, Mohajeri MH, Huber M, et al. Active immunization of mice with an Abeta-Hsp70 vaccine. Neurodegener Dis 2004; 1: 20–28.
- 48Nemirovsky A, Fisher Y, Baron R, Cohen IR, Monsonego A. Amyloid beta-HSP60 peptide conjugate vaccine treats a mouse model of Alzheimer's disease. Vaccine 2011; 29: 4043–4050.
- 49Dedmon MM, Christodoulou J, Wilson MR, Dobson CM. Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 2005; 280: 14733–14740.
- 50Roodveldt C, Bertoncini CW, Andersson A, et al. Chaperone proteostasis in Parkinson's disease: stabilization of the Hsp70/alpha-synuclein complex by Hip. EMBO J 2009; 28: 3758–3770.
- 51Labrador-Garrido A, Cejudo-Guillen M, Klippstein R, et al. Chaperoned amyloid proteins for immune manipulation: alpha-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype. Immun Inflamm Dis 2014; 2: 226–238.
- 52Meissner WG, Frasier M, Gasser T, et al. Priorities in Parkinson's disease research. Nat Rev Drug Discov 2011; 10: 377–393.
- 53FDA approves new drug for the chronic management of some urea cycle disorders. [cited 2015 Month 05]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm337639.htm
- 54Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem 2011; 286: 14941–14951.
- 55FDA Approval for Nilotinib. [cited 2015 Month 05]. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm216218.htm
- 56Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci Rep 2014; 4: 4874.
- 57Ko HS, Lee Y, Shin JH et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A 2010; 107: 16691–16696.
- 58Bieschke J, Russ J, Friedrich RP, et al. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A 2010; 107: 7710–7715.
- 59Schneeberger A, Mandler M, Mattner F, Schmidt W. Vaccination for Parkinson's disease. Parkinsonism Relat Disord 2012; 18 (Suppl 1): S11–S13.
- 60Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol 2014; 127: 861–879.
- 61Mandler M, Valera E, Rockenstein E, et al. Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 2015; 10: 10.
- 62Lalonde R, Strazielle C. Exploratory activity and motor coordination in old versus middle-aged C57BL/6J mice. Arch Gerontol Geriatr 2009; 49: 39–42.
- 63Metz GA, Schwab ME. Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice. Neuroscience 2004; 129: 563–574.
- 64Masliah E, Rockenstein E, Veinbergs I, et al. Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A 2001; 98: 12245–12250.
- 65Ubhi K, Inglis C, Mante M, et al. Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of alpha-synucleinopathy. Exp Neurol 2012; 234: 405–416.
- 66Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014; 6: 37.
- 67Wilcock DM. The usefulness and challenges of transgenic mouse models in the study of Alzheimer's disease. CNS Neurol Disord Drug Targets 2010; 9: 386–394.
- 68Stern MB, Lang A, Poewe W. Toward a redefinition of Parkinson's disease. Mov Disord 2012; 27: 54–60.
- 69Peran P, Cherubini A, Assogna F, et al. Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature. Brain 2010; 133: 3423–3433.
- 70Shi M, Bradner J, Hancock AM, et al. Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Ann Neurol 2011; 69: 570–580.
- 71Vaillancourt DE, Spraker MB, Prodoehl J, et al. High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology 2009; 72: 1378–1384.
- 72Evans JR, Mason SL, Williams-Gray CH, et al. The natural history of treated Parkinson's disease in an incident, community based cohort. J Neurol Neurosurg Psychiatry 2011; 82: 1112–1118.
- 73Schulz JB, Klockgether T, Petersen D, et al. Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 57: 1047–1056.
- 74Leber P. Slowing the progression of Alzheimer disease: methodologic issues. Alzheimer Dis Assoc Disord 1997; 11(Suppl 5): S10–S21; discussion S37-S19.
- 75Dickson DW, Fujishiro H, Orr C, et al. Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 2009; 15(Suppl 3): S1–S5.
- 76Sacchetti B, Baldi E, Lorenzini CA, Bucherelli C. Cerebellar role in fear-conditioning consolidation. Proc Natl Acad Sci U S A 2002; 99: 8406–8411.
- 77Jellinger KA, Seppi K, Wenning GK. Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 2005; 20(Suppl 12): S29–S36.
- 78Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998; 44: 415–422.
- 79Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 1998; 249: 180–182.
- 80Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045–2047.
- 81Eriksen JL, Dawson TM, Dickson DW, Petrucelli L. Caught in the act: alpha-synuclein is the culprit in Parkinson's disease. Neuron 2003; 40: 453–456.
- 82Ross OA, Braithwaite AT, Skipper LM, et al. Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann Neurol 2008; 63: 743–750.
- 83Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science 2003; 302: 841.
- 84Edwards TL, Scott WK, Almonte C, et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 2010; 74: 97–109.
- 85Gandhi S, Wood NW. Genome-wide association studies: the key to unlocking neurodegeneration? Nat Neurosci 2010; 13: 789–794.
- 86Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009; 41: 1303–1307.
- 87Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009; 41: 1308–1312.
- 88Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 2009; 65: 610–614.
- 89Fleming SM, Salcedo J, Fernagut PO, et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 2004; 24: 9434–9440.
- 90Fleming SM, Tetreault NA, Mulligan CK, Hutson CB, Masliah E, Chesselet MF. Olfactory deficits in mice overexpressing human wildtype alpha-synuclein. Eur J Neurosci 2008; 28: 247–256.
- 91Lotharius J, Brundin P. Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 2002; 3: 932–942.
- 92Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000; 287: 1265–1269.
- 93Rockenstein E, Crews L, Masliah E. Transgenic animal models of neurodegenerative diseases and their application to treatment development. Adv Drug Deliv Rev 2007; 59: 1093–1102.
- 94Lace G, Savva GM, Forster G, et al. Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study. Brain 2009; 132: 1324–1334.
- 95Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 2006; 116: 1744–1754.
- 96Jellinger KA, Kovacs GG. Clinico-pathological correlations in neurodegeneration. Acta Neuropathol 2011; 122: 115–116.
- 97Lim KL, Zhang CW. Molecular events underlying Parkinson's disease: an interwoven tapestry. Front Neurol 2013; 4: 33.
- 98Reynolds AD, Stone DK, Mosley RL, Gendelman HE. Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 2009; 182: 4137–4149.
- 99Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M. Alpha-Synuclein vaccination prevents the accumulation of Parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol 2013; 72: 624–645.