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CNS & Neurological Disorders - Drug Targets

Author(s): Sushma and Amal Chandra Mondal*

DOI: 10.2174/1871527321666211228100955

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Immunotherapeutic Approaches for the Treatment of Neurodegenerative Diseases: Challenges and Outcomes

Page: [404 - 416] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: Neurodegenerative diseases, being rapidly increasing disorders and the seventh leading cause of death worldwide, have been a great challenge for researchers, affecting cognition, motor activity and other body functioning due to neurodegeneration. Several neurodegenerative diseases are caused by aggregation of proteins which induce the alteration of neuronal function leading to cell death. These proteins are amyloid-β peptide, tau, α-synuclein, and mHTT, which cause Alzheimer’s disease, Frontotemporal dementia, Corticobasal degeneration, Progressive supranuclear palsy, Parkinson’s disease, Multiple system atrophy, Dementia with Lewy-body and Huntington’s disease. Currently available treatments only reduce symptoms and increase life sustainability; however, they possess side effects and are ineffective in curing the diseases.

Objective: Literature survey of neurodegenerative diseases and immunotherapeutic approaches is used to evaluate their pharmacological effects and future endeavours.

Methods: A literature search was performed to find the relevant articles related to neurodegenerative diseases and immunotherapies. Clinical trials data were analysed from clinicaltrial.com.

Results: According to the literature study, it was found that researchers have explored the effect of active and passive vaccines generated against amyloid-β, tau, α-synuclein and mHTT. Few clinical trials have shown severe side effects and terminated, despite that, few of them produced desirable effects for the treatment of AD and PD.

Conclusion: Several immunotherapeutic trials have shown promising outcomes against amyloid-β, tau and α-synuclein. In addition, various preclinical studies against mHTT and prion proteins are under scrutinization. These clinical outcomes indicate a promising role of immunotherapies against neurodegenerative diseases.

Keywords: Neurodegenerative diseases, amyloid-β, tau, α-synuclein, mhtt, alzheimer’s disease, parkinson’s disease, huntington’s disease.

Graphical Abstract

[1]
Feigin VL, Nichols E, Alam T, et al. Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(5): 459-80.
[http://dx.doi.org/10.1016/S1474-4422(18)30499-X] [PMID: 30879893]
[2]
Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci 2018; 21(10): 1332-40.
[http://dx.doi.org/10.1038/s41593-018-0235-9] [PMID: 30250260]
[3]
Solanki I, Parihar P, Parihar MSJNi. Neurodegenerative diseases: From available treatments to prospective herbal therapy. Neurochem Int 2016; 95: 100-8.
[http://dx.doi.org/10.1016/j.neuint.2015.11.001] [PMID: 26550708]
[4]
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 2007; 3(3): 186-91.
[http://dx.doi.org/10.1016/j.jalz.2007.04.381] [PMID: 19595937]
[5]
Association, 2019 Alzheimer’s disease facts and figures. Alzheimers Dement 2019; 15(3): 321-87.
[http://dx.doi.org/10.1016/j.jalz.2019.01.010]
[6]
Nichols E, Szoeke CEI, Vollset SE, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(1): 88-106.
[http://dx.doi.org/10.1016/S1474-4422(18)30403-4] [PMID: 30497964]
[7]
Veitch DP, Weiner MW, Aisen PS, et al. Understanding disease progression and improving Alzheimer’s disease clinical trials: Recent highlights from the Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement 2019; 15(1): 106-52.
[http://dx.doi.org/10.1016/j.jalz.2018.08.005] [PMID: 30321505]
[8]
Ryan NS, Rossor MN. Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomarkers Med 2010; 4(1): 99-112.
[http://dx.doi.org/10.2217/bmm.09.92] [PMID: 20387306]
[9]
Du X, Wang X, Geng M. Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener 2018; 7: 2.
[http://dx.doi.org/10.1186/s40035-018-0107-y] [PMID: 29423193]
[10]
Bekris L M, Galloway N M, Millard S, et al. Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease. Neurobiol Aging 2011; 32( 3): 13-23.
[11]
Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 2004; 62(11): 1984-9.
[http://dx.doi.org/10.1212/01.WNL.0000129697.01779.0A] [PMID: 15184601]
[12]
Thal DR, von Arnim C, Griffin WS, et al. Pathology of clinical and preclinical Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 2013; 263 (Suppl. 2): S137-45.
[http://dx.doi.org/10.1007/s00406-013-0449-5] [PMID: 24077890]
[13]
Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D. Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis 2012; 2012: 731526.
[http://dx.doi.org/10.1155/2012/731526] [PMID: 22690349]
[14]
Zempel H, Thies E, Mandelkow E, Mandelkow EM. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 2010; 30(36): 11938-50.
[http://dx.doi.org/10.1523/JNEUROSCI.2357-10.2010] [PMID: 20826658]
[15]
Lleó A. Current therapeutic options for Alzheimer’s disease. Curr Genomics 2007; 8(8): 550-8.
[http://dx.doi.org/10.2174/138920207783769549] [PMID: 19415128]
[16]
Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s disease: Are they effective? P&T 2010; 35(4): 208-11.
[PMID: 20498822]
[17]
Kovacs GG. Tauopathies. Handb Clin Neurol 2017; 145: 355-68.
[http://dx.doi.org/10.1016/B978-0-12-802395-2.00025-0] [PMID: 28987182]
[18]
Bang J, Spina S, Miller BLJTL. Frontotemporal dementia. Lancet 2015; 386(10004): 1672-82.
[http://dx.doi.org/10.1016/S0140-6736(15)00461-4] [PMID: 26595641]
[19]
Lee SE, Rabinovici GD, Mayo MC, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011; 70(2): 327-40.
[http://dx.doi.org/10.1002/ana.22424] [PMID: 21823158]
[20]
Williams DR, Lees AJJTLN. Progressive supranuclear palsy: Clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009; 8(3): 270-9.
[http://dx.doi.org/10.1016/S1474-4422(09)70042-0] [PMID: 19233037]
[21]
de Lau LM, Breteler MMJTLN. Epidemiology of Parkinson’s disease. Lancet Neurol 2006; 5(6): 525-35.
[http://dx.doi.org/10.1016/S1474-4422(06)70471-9] [PMID: 16713924]
[22]
Rani L, Mondal ACJM. Emerging concepts of mitochondrial dysfunction in Parkinson’s disease progression: Pathogenic and therapeutic implications. Mitochondrion 2020; 50: 25-34.
[http://dx.doi.org/10.1016/j.mito.2019.09.010] [PMID: 31654753]
[23]
Singh N, Pillay V, Choonara YE. Advances in the treatment of Parkinson’s disease. Prog Neurobiol 2007; 81(1): 29-44.
[http://dx.doi.org/10.1016/j.pneurobio.2006.11.009] [PMID: 17258379]
[24]
Coon EA, Singer W. Synucleinopathies. Continuum (Minneap Minn) 2020; 26(1): 72-92.
[http://dx.doi.org/10.1212/CON.0000000000000819] [PMID: 31996623]
[25]
Fanciulli A, Wenning GKJNEJM. Multiple-system atrophy. N Engl J Med 2015; 372(3): 249-63.
[http://dx.doi.org/10.1056/NEJMra1311488] [PMID: 25587949]
[26]
McKeith I. Dementia with Lewy bodies. Handb Clin Neurol 2007; 84: 531-48.
[http://dx.doi.org/10.1016/S0072-9752(07)84060-7] [PMID: 18808969]
[27]
Ross CA, Tabrizi SJJTLN. Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet Neurol 2011; 10(1): 83-98.
[http://dx.doi.org/10.1016/S1474-4422(10)70245-3] [PMID: 21163446]
[28]
Frank S. Treatment of Huntington’s disease. Neurotherapeutics 2014; 11(1): 153-60.
[http://dx.doi.org/10.1007/s13311-013-0244-z] [PMID: 24366610]
[29]
Cribbs DH, Agadjanyan MG. Immunotherapy for Alzheimer’s disease: Potential problems and possible solutions. Curr Immunol Rev 2005; 1(2): 139-55.
[http://dx.doi.org/10.2174/1573395054065179]
[30]
DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 2019; 14(1): 32.
[http://dx.doi.org/10.1186/s13024-019-0333-5] [PMID: 31375134]
[31]
Valera E, Spencer B, Masliah E. Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics 2016; 13(1): 179-89.
[http://dx.doi.org/10.1007/s13311-015-0397-z] [PMID: 26494242]
[32]
Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400(6740): 173-7.
[http://dx.doi.org/10.1038/22124] [PMID: 10408445]
[33]
Liu Y-H, Giunta B, Zhou H-D, Tan J, Wang Y-J. Immunotherapy for Alzheimer disease: The challenge of adverse effects. Nat Rev Neurol 2012; 8(8): 465-9.
[http://dx.doi.org/10.1038/nrneurol.2012.118] [PMID: 22751529]
[34]
Di Carlo M. Beta amyloid peptide: from different aggregation forms to the activation of different biochemical pathways. Eur Biophys J 2010; 39(6): 877-88.
[http://dx.doi.org/10.1007/s00249-009-0439-8] [PMID: 19305989]
[35]
Delrieu J, Ousset PJ, Voisin T, Vellas B. Amyloid beta peptide immunotherapy in Alzheimer disease. Rev Neurol (Paris) 2014; 170(12): 739-48.
[http://dx.doi.org/10.1016/j.neurol.2014.10.003] [PMID: 25459121]
[36]
Orgogozo J-M, Gilman S, Dartigues J-F, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61(1): 46-54.
[http://dx.doi.org/10.1212/01.WNL.0000073623.84147.A8] [PMID: 12847155]
[37]
Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372(9634): 216-23.
[http://dx.doi.org/10.1016/S0140-6736(08)61075-2] [PMID: 18640458]
[38]
Bayer AJ, Bullock R, Jones RW, et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 2005; 64(1): 94-101.
[http://dx.doi.org/10.1212/01.WNL.0000148604.77591.67] [PMID: 15642910]
[39]
Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64(9): 1553-62.
[http://dx.doi.org/10.1212/01.WNL.0000159740.16984.3C] [PMID: 15883316]
[40]
Münch G, Robinson SR. Potential neurotoxic inflammatory responses to Abeta vaccination in humans. J Neural Transm (Vienna) 2002; 109(7-8): 1081-7.
[http://dx.doi.org/10.1007/s007020200091] [PMID: 12111445]
[41]
Maarouf CL, Daugs ID, Kokjohn TA, et al. The biochemical aftermath of anti-amyloid immunotherapy. Mol Neurodegener 2010; 5(1): 39.
[http://dx.doi.org/10.1186/1750-1326-5-39] [PMID: 20929585]
[42]
Serrano-Pozo A, William CM, Ferrer I, et al. Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology. Brain 2010; 133(Pt 5): 1312-27.
[http://dx.doi.org/10.1093/brain/awq056] [PMID: 20360050]
[43]
Boche D, Donald J, Love S, et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol 2010; 120(1): 13-20.
[http://dx.doi.org/10.1007/s00401-010-0705-y] [PMID: 20532897]
[44]
Arai H, Suzuki H, Yoshiyama T, et al. P1-338: Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC-001]) and the QS-21 adjuvant in Japanese individuals with mild-to-moderate Alzheimer’s disease: A phase IIa, multicenter, randomized, adjuvant and pl. Alzheimers Dement 2013; 9: 282-P282.
[http://dx.doi.org/10.1016/j.jalz.2013.05.564]
[45]
Pasquier F, Sadowsky C, Holstein A, et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s Disease. J Alzheimers Dis 2016; 51(4): 1131-43.
[http://dx.doi.org/10.3233/JAD-150376] [PMID: 26967206]
[46]
Hull M, Sadowsky C, Arai H, et al. Long-term extensions of randomized vaccination trials of ACC-001 and QS-21 in mild to moderate Alzheimer’s disease. Curr Alzheimer Res 2017; 14(7): 696-708.
[http://dx.doi.org/10.2174/1567205014666170117101537] [PMID: 28124589]
[47]
Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin 2010; 6(11): 948-52.
[http://dx.doi.org/10.4161/hv.6.11.13217] [PMID: 20980801]
[48]
Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W. Development of AFFITOPE vaccines for Alzheimer’s disease (AD)-from concept to clinical testing. J Nutr Health Aging 2009; 13(3): 264-7.
[http://dx.doi.org/10.1007/s12603-009-0070-5] [PMID: 19262965]
[49]
Schneeberger A, Hendrix S, Ellison N, Bürger V, Dubois B. Additional results from a phase ii study to assess the clinical and immunological activity, safety, and tolerability of affitope® ad02 in patients with early Alzheimer's disease (AD). Alzheimers Dement 2015; 11(7S_Part_6): 276-6.
[50]
Wiessner C, Wiederhold KH, Tissot AC, et al. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci 2011; 31(25): 9323-31.
[http://dx.doi.org/10.1523/JNEUROSCI.0293-11.2011] [PMID: 21697382]
[51]
Winblad B, Andreasen N, Minthon L, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: Randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012; 11(7): 597-604.
[http://dx.doi.org/10.1016/S1474-4422(12)70140-0] [PMID: 22677258]
[52]
Farlow MR, Andreasen N, Riviere ME, et al. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res Ther 2015; 7(1): 23.
[http://dx.doi.org/10.1186/s13195-015-0108-3] [PMID: 25918556]
[53]
Vandenberghe R, Riviere ME, Caputo A, et al. Active Aβ immunotherapy CAD106 in Alzheimer’s disease: A phase 2b study. Alzheimers Dement (N Y) 2016; 3(1): 10-22.
[http://dx.doi.org/10.1016/j.trci.2016.12.003] [PMID: 29067316]
[54]
Muhs 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 USA 2007; 104(23): 9810-5.
[http://dx.doi.org/10.1073/pnas.0703137104] [PMID: 17517595]
[55]
Wang CY, Wang PN, Chiu MJ, et al. UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement (N Y) 2017; 3(2): 262-72.
[http://dx.doi.org/10.1016/j.trci.2017.03.005] [PMID: 29067332]
[56]
Lacosta AM, Pascual-Lucas M, Pesini P, et al. Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer’s disease: A randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res Ther 2018; 10(1): 12.
[http://dx.doi.org/10.1186/s13195-018-0340-8] [PMID: 29378651]
[57]
Brody DL, Holtzman DM. Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci 2008; 31: 175-93.
[http://dx.doi.org/10.1146/annurev.neuro.31.060407.125529] [PMID: 18352830]
[58]
Schilling S, Rahfeld JU, Lues I, Lemere CA. Passive Aβ Immunotherapy: Current Achievements and Future Perspectives. Molecules 2018; 23(5): E1068.
[http://dx.doi.org/10.3390/molecules23051068] [PMID: 29751505]
[59]
Gardberg AS, Dice LT, Ou S, et al. Molecular basis for passive immunotherapy of Alzheimer’s disease. Proc Natl Acad Sci USA 2007; 104(40): 15659-64.
[http://dx.doi.org/10.1073/pnas.0705888104] [PMID: 17895381]
[60]
Miles LA, Crespi GA, Doughty L, Parker MW. Bapineuzumab captures the N-terminus of the Alzheimer’s disease amyloid-beta peptide in a helical conformation. Sci Rep 2013; 3: 1302.
[http://dx.doi.org/10.1038/srep01302] [PMID: 23416764]
[61]
Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73(24): 2061-70.
[http://dx.doi.org/10.1212/WNL.0b013e3181c67808] [PMID: 19923550]
[62]
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370(4): 322-33.
[http://dx.doi.org/10.1056/NEJMoa1304839] [PMID: 24450891]
[63]
Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012; 11(3): 241-9.
[http://dx.doi.org/10.1016/S1474-4422(12)70015-7] [PMID: 22305802]
[64]
Abushouk AI, Elmaraezy A, Aglan A, et al. Bapineuzumab for mild to moderate Alzheimer’s disease: A meta-analysis of randomized controlled trials. BMC Neurol 2017; 17(1): 66.
[http://dx.doi.org/10.1186/s12883-017-0850-1] [PMID: 28376794]
[65]
Crespi GA, Hermans SJ, Parker MW, Miles LA. Molecular basis for mid-region amyloid-β capture by leading Alzheimer’s disease immunotherapies. Sci Rep 2015; 5: 9649.
[http://dx.doi.org/10.1038/srep09649] [PMID: 25880481]
[66]
DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-A β antibody alters CNS and plasma A β clearance and decreases brain A β burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98(15): 8850-5.
[http://dx.doi.org/10.1073/pnas.151261398] [PMID: 11438712]
[67]
Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 2012; 8(4): 261-71.
[http://dx.doi.org/10.1016/j.jalz.2011.09.224] [PMID: 22672770]
[68]
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370(4): 311-21.
[http://dx.doi.org/10.1056/NEJMoa1312889] [PMID: 24450890]
[69]
Uenaka K, Nakano M, Willis BA, et al. Comparison of pharmacokinetics, pharmacodynamics, safety, and tolerability of the amyloid β monoclonal antibody solanezumab in Japanese and white patients with mild to moderate Alzheimer disease. Clin Neuropharmacol 2012; 35(1): 25-9.
[http://dx.doi.org/10.1097/WNF.0b013e31823a13d3] [PMID: 22134132]
[70]
Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci 2012; 32(28): 9677-89.
[http://dx.doi.org/10.1523/JNEUROSCI.4742-11.2012] [PMID: 22787053]
[71]
Yang T, Dang Y, Ostaszewski B, et al. Target engagement in an Alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Ann Neurol 2019; 86(2): 215-24.
[http://dx.doi.org/10.1002/ana.25513] [PMID: 31168802]
[72]
Guthrie H, Honig LS, Lin H, et al. Safety, tolerability, and pharmacokinetics of crenezumab in patients with mild-to-moderate Alzheimer’s disease treated with escalating doses for up to 133 weeks. J Alzheimers Dis 2020; 76(3): 967-79.
[http://dx.doi.org/10.3233/JAD-200134] [PMID: 32568196]
[73]
Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018; 90(21): e1889-97.
[http://dx.doi.org/10.1212/WNL.0000000000005550] [PMID: 29695589]
[74]
Tariot PN, Lopera F, Langbaum JB, et al. The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimers Dement (N Y) 2018; 4: 150-60.
[http://dx.doi.org/10.1016/j.trci.2018.02.002] [PMID: 29955659]
[75]
Novakovic D, Feligioni M, Scaccianoce S, et al. Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Des Devel Ther 2013; 7: 1359-64.
[PMID: 24255592]
[76]
Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69(2): 198-207.
[http://dx.doi.org/10.1001/archneurol.2011.1538] [PMID: 21987394]
[77]
Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017; 9(1): 95.
[http://dx.doi.org/10.1186/s13195-017-0318-y] [PMID: 29221491]
[78]
Kastanenka KV, Bussiere T, Shakerdge N, et al. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. J Neurosci 2016; 36(50): 12549-58.
[http://dx.doi.org/10.1523/JNEUROSCI.2080-16.2016] [PMID: 27810931]
[79]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618): 50-6.
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
[80]
Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep 2018; 8(1): 6412.
[http://dx.doi.org/10.1038/s41598-018-24501-0] [PMID: 29686315]
[81]
Logovinsky V, Satlin A, Lai R, et al. Safety and tolerability of BAN2401-a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther 2016; 8(1): 14.
[http://dx.doi.org/10.1186/s13195-016-0181-2] [PMID: 27048170]
[82]
Söllvander S, Nikitidou E, Gallasch L, et al. The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death. J Neuroinflammation 2018; 15(1): 98.
[http://dx.doi.org/10.1186/s12974-018-1134-4] [PMID: 29592816]
[83]
Tucker S, Möller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 2015; 43(2): 575-88.
[http://dx.doi.org/10.3233/JAD-140741] [PMID: 25096615]
[84]
Landen JW, Cohen S, Billing CB Jr, et al. Multiple-dose ponezumab for mild-to-moderate Alzheimer’s disease: Safety and efficacy. Alzheimers Dement (N Y) 2017; 3(3): 339-47.
[http://dx.doi.org/10.1016/j.trci.2017.04.003] [PMID: 29067341]
[85]
Landen J, Cohen S, Billing C, et al. P4-208: Safety, efficacy, pharmacokinetics and pharmacodynamics of multiple doses of Ponezumab in subjects with mild-to-moderate Alzheimer's disease Alzheimers Dement 2012; 8(4S_Part_19 ): 708-8.
[86]
Davtyan H, Ghochikyan A, Petrushina I, et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: Prelude to a clinical trial. J Neurosci 2013; 33(11): 4923-34.
[http://dx.doi.org/10.1523/JNEUROSCI.4672-12.2013] [PMID: 23486963]
[87]
Iqbal K, Alonso AdelC, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 2005; 1739(2-3): 198-210.
[http://dx.doi.org/10.1016/j.bbadis.2004.09.008] [PMID: 15615638]
[88]
DeVos SL, Corjuc BT, Oakley DH, et al. Synaptic tau seeding precedes tau pathology in human Alzheimer’s disease brain. Front Neurosci 2018; 12: 267.
[http://dx.doi.org/10.3389/fnins.2018.00267] [PMID: 29740275]
[89]
Zilkova M, Nolle A, Kovacech B, et al. Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation. Acta Neuropathol Commun 2020; 8(1): 74.
[http://dx.doi.org/10.1186/s40478-020-00948-z] [PMID: 32471486]
[90]
Novak P, Schmidt R, Kontsekova E, et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimers Res Ther 2018; 10(1): 108.
[http://dx.doi.org/10.1186/s13195-018-0436-1] [PMID: 30355322]
[91]
Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: A randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol 2017; 16(2): 123-34.
[http://dx.doi.org/10.1016/S1474-4422(16)30331-3] [PMID: 27955995]
[92]
Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in- man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 2014; 6(4): 44.
[http://dx.doi.org/10.1186/alzrt278] [PMID: 25478017]
[93]
West T, Hu Y, Verghese PB, et al. Preclinical and clinical development of ABBV-8E12, a humanized anti-tau antibody, for treatment of Alzheimer’s disease and other tauopathies. J Prev Alzheimers Dis 2017; 4(4): 236-41.
[PMID: 29181488]
[94]
Qureshi IA, Tirucherai G, Ahlijanian MK, Kolaitis G, Bechtold C, Grundman M. A randomized, single ascending dose study of intravenous BIIB092 in healthy participants. Alzheimers Dement (N Y) 2018; 4: 746-55.
[http://dx.doi.org/10.1016/j.trci.2018.10.007] [PMID: 30581980]
[95]
Boxer AL, Qureshi I, Ahlijanian M, et al. Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: A randomised, placebo-controlled, multiple ascending dose phase 1b trial. Lancet Neurol 2019; 18(6): 549-58.
[http://dx.doi.org/10.1016/S1474-4422(19)30139-5] [PMID: 31122495]
[96]
Kerchner G A, Ayalon G, Brunstein F, et al. A phase I study to evaluate the safety and tolerability of ro7105705 in healthy volunteers and patients with mild-to-moderate ad. Alzheimers & Dement 2017; 13 (7S_Part_12): 601-1.
[97]
Rocha EM, De Miranda B, Sanders LH. Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 2018; 109(Pt B): 249-57.
[http://dx.doi.org/10.1016/j.nbd.2017.04.004] [PMID: 28400134]
[98]
Vaikath NN, Hmila I, Gupta V, Erskine D, Ingelsson M, El-Agnaf OMA. Antibodies against alpha-synuclein: Tools and therapies. J Neurochem 2019; 150(5): 612-25.
[http://dx.doi.org/10.1111/jnc.14713] [PMID: 31055836]
[99]
Volc D, Poewe W, Kutzelnigg A, et al. Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson’s disease: A randomised, single-blinded, phase 1 trial. Lancet Neurol 2020; 19(7): 591-600.
[http://dx.doi.org/10.1016/S1474-4422(20)30136-8] [PMID: 32562684]
[100]
Meissner WG, Traon APL, Foubert-Samier A, et al. A phase 1 randomized trial of specific active α-synuclein immunotherapies pd01a and pd03a in multiple system atrophy. Mov Disord 2020; 35(11): 1957-65.
[http://dx.doi.org/10.1002/mds.28218] [PMID: 32882100]
[101]
Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord 2017; 32(2): 211-8.
[http://dx.doi.org/10.1002/mds.26878] [PMID: 27886407]
[102]
Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti–α-synuclein monoclonal antibody, in patients with Parkinson disease: A randomized clinical trial. JAMA Neurol 2018; 75(10): 1206-14.
[http://dx.doi.org/10.1001/jamaneurol.2018.1487] [PMID: 29913017]
[103]
Brys M, Fanning L, Hung S, et al. Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054. Mov Disord 2019; 34(8): 1154-63.
[http://dx.doi.org/10.1002/mds.27738] [PMID: 31211448]
[104]
Weihofen A, Liu Y, Arndt JW, et al. Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson’s disease models. Neurobiol Dis 2019; 124: 276-88.
[http://dx.doi.org/10.1016/j.nbd.2018.10.016] [PMID: 30381260]
[105]
Schofield DJ, Irving L, Calo L, et al. Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo . Neurobiol Dis 2019; 132: 104582.
[http://dx.doi.org/10.1016/j.nbd.2019.104582] [PMID: 31445162]
[106]
LaGanke C, Samkoff L, Edwards K, et al. Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial. Neurol Neuroimmunol Neuroinflamm 2017; 4(4): e367.
[http://dx.doi.org/10.1212/NXI.0000000000000367] [PMID: 28642891]
[107]
Ramsingh AI, Manley K, Rong Y, Reilly A, Messer A. Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington’s disease. Hum Mol Genet 2015; 24(21): 6186-97.
[http://dx.doi.org/10.1093/hmg/ddv335] [PMID: 26307082]
[108]
Butler DC, Messer A. Bifunctional anti-huntingtin proteasome-directed intrabodies mediate efficient degradation of mutant huntingtin exon 1 protein fragments. PLoS One 2011; 6(12): e29199.
[http://dx.doi.org/10.1371/journal.pone.0029199] [PMID: 22216210]
[109]
Snyder-Keller A, McLear JA, Hathorn T, Messer A, Neurology E. Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice. J Neuropathol Exp Neurol 2010; 69(10): 1078-85.
[http://dx.doi.org/10.1097/NEN.0b013e3181f530ec] [PMID: 20838238]
[110]
Southwell AL, Khoshnan A, Dunn DE, Bugg CW, Lo DC, Patterson PHJJN. Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity. J Neurosci 2008; 28(36): 9013-20.
[http://dx.doi.org/10.1523/JNEUROSCI.2747-08.2008] [PMID: 18768695]
[111]
Southwell AL, Ko J, Patterson PHJJN. Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington’s disease. J Neurosci 2009; 29(43): 13589-602.
[http://dx.doi.org/10.1523/JNEUROSCI.4286-09.2009] [PMID: 19864571]
[112]
Amaro IA, Henderson LA. An intrabody drug (rAAV6-INT41) reduces the binding of N-terminal Huntingtin fragment (s) to DNA to basal levels in PC12 cells and delays cognitive loss in the R6/2 animal model. J Neurodegener Dis 2016; 2016: 7120753.
[113]
Sigurdson CJ, Bartz JC, Glatzel M. Cellular and molecular mechanisms of prion disease. Annu Rev Pathol 2019; 14: 497-516.
[http://dx.doi.org/10.1146/annurev-pathmechdis-012418-013109] [PMID: 30355150]
[114]
Ma Y, Ma J. Immunotherapy against prion disease. Pathogens 2020; 9(3): E216.
[http://dx.doi.org/10.3390/pathogens9030216] [PMID: 32183309]
[115]
Roettger Y, Du Y, Bacher M, Zerr I, Dodel R, Bach J-PJNRN. Immunotherapy in prion disease. Nat Rev Neurol 2013; 9(2): 98-105.
[http://dx.doi.org/10.1038/nrneurol.2012.258] [PMID: 23247613]
[116]
Kwon S, Iba M, Kim C, Masliah E. Immunotherapies for Aging-Related Neurodegenerative Diseases-Emerging Perspectives and New Targets. Neurotherapeutics 2020; 17(3): 935-54.
[http://dx.doi.org/10.1007/s13311-020-00853-2] [PMID: 32347461]
[117]
Spires-Jones TL, Mielke ML, Rozkalne A, et al. Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease. Neurobiol Dis 2009; 33(2): 213-20.
[http://dx.doi.org/10.1016/j.nbd.2008.10.011] [PMID: 19028582]
[118]
Carlson C, Siemers E, Hake A, et al. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer’s disease. Alzheimers Dement (Amst) 2016; 2: 75-85.
[http://dx.doi.org/10.1016/j.dadm.2016.02.004] [PMID: 27239538]
[119]
Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res Ther 2018; 10(1): 96.
[http://dx.doi.org/10.1186/s13195-018-0424-5] [PMID: 30231896]
[120]
Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 2015; 21(6): 394-402.
[http://dx.doi.org/10.1016/j.molmed.2015.03.003] [PMID: 25846560]