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

Sushma; Amal   Chandra   Mondal
doi:10.2174/1871527321666211228100955
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.
« Previous Next »
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]
Rights & Permissions Print Cite
Article Metrics
5
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1871527321666211228100955	Print ISSN 1871-5273
Publisher Name Bentham Science Publisher	Online ISSN 1996-3181
CNS & Neurological Disorders - Drug Targets

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

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
