RESUMEN
BACKGROUND: Immunotherapy targeting the amyloid-ß (Aß) peptide is a promising strategy for the treatment of Alzheimer's disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aß40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial. METHODS: A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50-85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aß40 antibodies in plasma. RESULTS: Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aß40 antibodies. CONCLUSIONS: ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer/uso terapéutico , Péptidos beta-Amiloides/inmunología , Inmunogenicidad Vacunal , Fragmentos de Péptidos/inmunología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Vacunas contra el Alzheimer/efectos adversos , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Dominios Proteicos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. METHODS: We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198. FINDINGS: This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. INTERPRETATION: AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. FUNDING: AXON Neuroscience SE.
Asunto(s)
Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer/farmacología , Inmunoterapia/métodos , Evaluación de Resultado en la Atención de Salud , Proteínas tau/inmunología , Anciano , Anciano de 80 o más Años , Vacunas contra el Alzheimer/efectos adversos , Método Doble Ciego , Femenino , Humanos , Inmunoterapia/efectos adversos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Amyloid deposit and hyperphosphorylated Tau protein contribute to pathological changes seen in Alzheimer's disease (AD) and imply that removal may reverse the cognitive decline. Immunotherapy is a potential way of reducing the load of amyloid or Tau in the brain. AREAS COVERED: This review summarizes recent clinical trials that have investigated immunotherapy to treat AD and its potential mechanisms. In addition, the potential opportunities as well as challenges of immunotherapy for AD in clinical trials are also discussed. EXPERT OPINION: Amyloid-based immunotherapy for AD is a novel method with potential; however, some clinical trials were terminated because of the adverse effects. Further studies need to determine the following questions: (i) which is better, passive, or active immunotherapy; (ii) which could be used for the vaccine, amyloid or Tau; (iii) which is better, short- or long-antigen vaccine; and (iv) the route of delivery for antigen or antibody.
Asunto(s)
Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/inmunología , Ensayos Clínicos como Asunto , Inmunoterapia/métodos , Enfermedad de Alzheimer/inmunología , Vacunas contra el Alzheimer/efectos adversos , Vacunas contra el Alzheimer/inmunología , Vacunas contra el Alzheimer/uso terapéutico , Amiloide/análisis , Amiloide/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Péptidos beta-Amiloides/efectos adversos , Péptidos beta-Amiloides/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Especificidad de Anticuerpos , Sistemas de Liberación de Medicamentos , Humanos , Inmunización/efectos adversos , Inmunización/métodos , Inmunización Pasiva/efectos adversos , Inmunización Pasiva/métodos , Inmunoterapia/efectos adversos , Inmunoterapia Activa/efectos adversos , Inmunoterapia Activa/métodos , Fosforilación , Placa Amiloide/inmunología , Intercambio Plasmático , Plasmaféresis , Procesamiento Proteico-Postraduccional , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas tau/inmunología , Proteínas tau/metabolismoAsunto(s)
Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer/inmunología , Vacunas contra el Alzheimer/uso terapéutico , Péptidos beta-Amiloides/antagonistas & inhibidores , Inmunoglobulinas Intravenosas/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Vacunas contra el Alzheimer/efectos adversos , Amiloide/antagonistas & inhibidores , Amiloide/química , Amiloide/inmunología , Amiloide/metabolismo , Péptidos beta-Amiloides/efectos adversos , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/uso terapéutico , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Ensayos Clínicos como Asunto , Humanos , Inmunoglobulinas Intravenosas/economía , Ratones , Proteínas tau/antagonistas & inhibidores , Proteínas tau/química , Proteínas tau/metabolismoRESUMEN
Amyloid-ß (Aß) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aß in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aß(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aß(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aß immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aß/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Vacunas contra el Alzheimer/efectos adversos , Vacunas contra el Alzheimer/uso terapéutico , Péptidos beta-Amiloides/inmunología , Ensayos Clínicos como Asunto/métodos , Inmunización Pasiva/métodos , Inmunoterapia Activa/métodos , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ensayos Clínicos como Asunto/efectos adversos , Modelos Animales de Enfermedad , Humanos , Modelos InmunológicosRESUMEN
We recently demonstrated that newly developed non-viral amyloid-ß (Aß) DNA vaccines are safe and effective in reducing Aß burdens in the brains of Alzheimer's disease (AD) model mice. The present study was undertaken to examine whether DNA vaccines effectively and safely reduce Aß deposition in the brain of rhesus monkeys. For this purpose, DNA vaccines or empty vector at a dose of 3 mg were injected intramuscularly on a biweekly basis into rhesus monkeys (15-18 years old). Before and during vaccination, blood was drawn once a month and used for hematological and biochemical examinations. Six months after the first vaccination, it was demonstrated that anti-Aß antibodies in plasma of vaccinated monkeys were significantly elevated than that of control monkeys. Immunohistochemical examinations revealed that DNA vaccination reduced the Aß burden to approximately 50% of that found in control monkeys (p=0.026). There was neither inflammation nor microhemorrhage in the brain and no significant changes in cytokine and chemokine levels in the blood throughout the observation period. Taken together, DNA vaccination to monkeys is safe and effective in Aß reduction and provides useful information for performing preclinical and clinical trials.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inmunología , Vacunas contra el Alzheimer/inmunología , Péptidos beta-Amiloides/inmunología , Animales , Western Blotting , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , ADN Viral/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunohistoquímica , Macaca mulatta , Masculino , Estadísticas no ParamétricasRESUMEN
Over the past few years, new ways of fighting Alzheimer's disease have emerged based on stimulating the immunitary defence system of the patients. To avoid toxicity and autoimmune response related to the Aß[1-42] peptide immunotherapy, in the last decade a large number of works aimed at identifying new classes of safe Aß derivatives by modifying the full length ß-amyloid form. In strict agreement with the purposes of the sequence-simplification technology, Aß[1-16], Aß[13-28] and Aß[25-42] fragments were selected in order to retain the major immunogenic sites of the Aß[1-42] peptide, and corresponding simplified forms were designed and synthesized. All glycinated Aß derivatives showed immunogenic and antigenic properties similar to the parent Aß[1-42] peptide, and raised antibodies were all able to cross-recognize both Aß[1-42] and Aß[1-40] synthetic structures. All Aß simplified forms showed reduced fibrillogenic and inflammatory properties. In particular, the Aß[13-28]+G form failed to induce IFN-γ production thus suggesting that this molecule could represent a good candidate for potentially safer AD vaccine therapy.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Vacunas contra el Alzheimer/efectos adversos , Vacunas contra el Alzheimer/inmunología , Péptidos beta-Amiloides/inmunología , HumanosRESUMEN
Active immunization with amyloid-ß (Aß) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Aß(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Aß(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, Aß(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aß(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Aß(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Aß(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aß(1-42)-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aß(1-42)/CFA. Thus, this study identifies adjuvant effects of Aß(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aß immunotherapy.
Asunto(s)
Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/inmunología , Inmunidad Innata/inmunología , Trastornos de la Memoria/inmunología , Fragmentos de Péptidos/inmunología , Vacunación/efectos adversos , Adyuvantes Inmunológicos/farmacología , Vacunas contra el Alzheimer/inmunología , Péptidos beta-Amiloides/farmacología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Separación Celular , Citocinas/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Adyuvante de Freund/inmunología , Adyuvante de Freund/farmacología , Humanos , Macrófagos/inmunología , Trastornos de la Memoria/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Fragmentos de Péptidos/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 2/biosíntesis , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/biosíntesis , Receptor Toll-Like 4/inmunologíaRESUMEN
Recent progress in biological studies on Alzheimer's disease (AD) could lead to a new strategy for its treatment. One of the representative and leading therapies is passive and active immunotherapy. The first active immunotherapy using the full length of Abeta protein was stopped due to the serious side-effect of encephalitis. Currently, a new revised immunotherapy using humanized mouse monoclonal antiserum against a part of Abeta protein is under clinical trials. Here, future advance concerning AD treatment as well as the present situation will be reviewed.
Asunto(s)
Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer , Diseño de Fármacos , Inmunoterapia , Enfermedad de Alzheimer/etiología , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides , Animales , Colina O-Acetiltransferasa , Inhibidores de la Colinesterasa/uso terapéutico , HumanosRESUMEN
The important pathognomonic features of Alzheimer disease (AD) brain are the occurrence of abundant neurofibrillary tangles (NFTs) in neurons and presence of extracellular deposits of beta-amyloid (Abeta)- senile plaques. In the early 1980s, the NFTs were characterized, and cerebral amyloid was purified; further the amino acid sequences of the tau protein in the NFTs and of Abeta were identified. Immunohistochemical studies with antibodies to tau and Abeta revealed that extracellular accumulation of Abeta precedes that of tau in neurons. Molecular genetic studies revealed that abnormal gene mutations of familial AD accelerate Abeta production. On the basis of these findings, the amyloid cascade hypothesis that Abeta accumulation is the primary cause of neuronal degeneration and induces accumulation of tau in the AD brain was proposed and widely accepted. Thus, on the basis of this hypothesis, transgenic AD mice were treated with Abeta vaccine; the Abeta amyloid plaques were eliminated, and a dramatic improvement of the behavioral deficits was observed in the treated mice. The great success of preclinical studies promoted clinical trials of the Abeta vaccine in AD patients. However,the clinical trials were discontinued because of the occurrence of severe meningoencephalitis. Postmortem examination of the brains of the vaccinated patients with high titer of the anti- Abeta antibody in the serum revealed elimination of the Abeta plaques along with presence of cerebral inflammation. However, in autopsy-proven cases, assessment of the clinical and cognitive functions of the patients did not provide any evidence for improved survival or prolongation of the time to severe dementia. Thus, anti-Abeta antibody could eliminate the accumulated Abeta but could not rescue the degenerated neurons. Thus, the AD treatment strategy should be converted from repair and cure of AD to prevention. Anti-Abeta therapy must be started at the preclinical stage, and it is necessary to focus on tau and other proteins, mitochondria, glial cells, and other factors that influence the degeneration of neurons.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Vacunas contra el Alzheimer , Péptidos beta-Amiloides/inmunología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer/administración & dosificación , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Apolipoproteína E4/genética , Encéfalo/metabolismo , Encéfalo/patología , Ensayos Clínicos como Asunto , Humanos , Meningoencefalitis/etiología , Ratones , Mutación , Degeneración Nerviosa , Ovillos Neurofibrilares/metabolismo , Presenilinas/genética , Proteínas tau/metabolismoRESUMEN
Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Vacunas contra el Alzheimer , Péptidos beta-Amiloides/antagonistas & inhibidores , Vacunas de ADN , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Enfermedad de Alzheimer/inmunología , Vacunas contra el Alzheimer/efectos adversos , Vacunas contra el Alzheimer/genética , Vacunas contra el Alzheimer/uso terapéutico , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/inmunología , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Ensayos Clínicos como Asunto/estadística & datos numéricos , Humanos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Vacunación/métodos , Vacunación/tendencias , Vacunas de ADN/efectos adversos , Vacunas de ADN/inmunología , Vacunas de ADN/uso terapéuticoRESUMEN
Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression. Amyloid-beta (Abeta) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Abeta as a target for treatment. Abeta immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Abeta vaccine was halted due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Abeta immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Abeta immunotherapy are underway. In this review, we will provide an update of Abeta immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Abeta immunotherapy for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Vacunas contra el Alzheimer/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Inmunoterapia/métodos , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Vacunas contra el Alzheimer/efectos adversos , Vacunas contra el Alzheimer/uso terapéutico , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/inmunología , Encéfalo/fisiopatología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Modelos Animales de Enfermedad , Humanos , Inmunoterapia/tendencias , Ratones , Ratones Transgénicos/genética , Ratones Transgénicos/inmunología , Ratones Transgénicos/metabolismo , Placa Amiloide/efectos de los fármacos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Vacunación/métodos , Vacunación/tendenciasRESUMEN
Few topics in the field of Alzheimer's disease (AD) research have brought about the level of excitement and interest as the role of inflammation and immunity in the pathobiology and treatment of the disease. In this special issue of the journal, experts in the field give their views on how inflammatory processes and the immune system intersect- at both etiological and treatment levels- with disease biology. Collectively, nearly three decades of work are covered in this special issue, beginning with the first epidemiologic studies that showed an inverse risk relationship between AD and use of non-steroidal anti-inflammatory drugs, and ending with "immunotherapy" approaches and recent studies examining the roles of innate immune cells including microglia and peripheral mononuclear phagocytes in AD. Despite considerable work in this area, many important questions remain concerning the nature and timing of immune/inflammatory responses in the context of AD, and at what point and how to therapeutically intervene.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Autoinmunidad/fisiología , Encefalitis/inmunología , Encefalitis/fisiopatología , Sistema Inmunológico/fisiopatología , Enfermedad de Alzheimer/tratamiento farmacológico , Vacunas contra el Alzheimer/efectos adversos , Vacunas contra el Alzheimer/aislamiento & purificación , Vacunas contra el Alzheimer/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Autoinmunidad/efectos de los fármacos , Encefalitis/tratamiento farmacológico , Sistema Inmunológico/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/fisiología , Microglía/efectos de los fármacos , Microglía/inmunologíaRESUMEN
Current treatment options for Alzheimer's disease (AD) exert only a short-lived effect on disease symptoms. Active and passive immunotherapy have both been shown to be effective in clearing plaques, removing beta-amyloid (Abeta) and improving behaviour in animal models of AD. Although the first active immunization trial in humans was discontinued because of severe adverse effects, several new approaches are currently being investigated in clinical trials. Recently, commercially available intravenous immunoglobulins (IVIG) have been used in small pilot trials for the treatment of patients with AD, based on the hypothesis that IVIG contains naturally occurring autoantibodies (nAbs-Abeta) that specifically recognize and block the toxic effects of Abeta. Furthermore, these nAbs-Abeta are reduced in AD patients compared with healthy controls, supporting the notion of replacement with IVIG. Beyond the occurrence of nAbs-Abeta, evidence for several other mechanisms associated with IVIG in AD has been reported in preclinical experiments and clinical studies. In 2009, a phase III clinical trial involving more than 360 AD patients was initiated and may provide conclusive evidence for the effect of IVIG as a treatment option for AD in 2011. In this article, we review the current knowledge and scientific rationale for using IVIG in patients with AD and other neurodegenerative disorders.
Asunto(s)
Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/inmunología , Cognición , Medicina Basada en la Evidencia , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Factores Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Degeneración Nerviosa , Resultado del TratamientoRESUMEN
Dementia is one of the most important health problems in the aging populations. The most frequent cause of it is Alzheimer's disease (AD) which is characterized by intracellular neuro-fibrillary tangles (NFT) and the extracellular senile plaques. The NFTs are mainly formed by the hyperphosphorylated microtubule-binding protein, the tau, while the senile plaques are composed of beta-amyloid protein cleaved from the amyloid precursor protein (APP) by the beta- and gamma-secretases. The pharmacotherapy of AD consists of symptomatic and disease-modifying therapies. The most frequently used therapeutic agents are the nootropic drugs supported by personal rather evidence based experiences. The leading-edge therapy of AD at present is the inhibition of the acetylcholine-esterase enzyme (AChEI) with mainly cognitive symptomatic and weak disease-modifying effects; they are licensed in the mild and middle stages of AD (MMSE 26-10), but their effect is proved in the severe stage of the disease and they are effective in the management of the neuropsychiatric symptoms too. Memantine (which is an inhibitor of the N-metil-D-aspartate receptor) is used in the middle and severe stages of AD and it can be effectively combined with AChEIs. The future therapy of AD will possibly be a "causative" therapy. The most frequent directions are therapies aiming to decrease the production or the deposition of beta-amyloid peptide. The active vaccination study of AN-1792 was terminated because of immunological side-effects, but several active and passive immunisation therapies are in development nowadays. It is also possible to inhibit the aggregation of the beta-amyloid peptide with peptide fragments or with Cu2+ and Zn2+ ion chelators. A promising direction is the inhibition of the enzymes responsible for the production of the beta-amyloid peptide: beta-secretase inhibitors with low molecular weight and penetrability through the blood-brain barrier are developed while the inhibitors of the gamma-secretase (some of them are the derivatives of the non-steroid anti-inflammatory drug ibuprofen) are tested in phase III trials. The inhibition of NFT formation might be promising too and inhibitors of the enzymes responsible for the hyperphosphorylation of the tau (like the glycogen synthase kinase-3) are in develo ment. Several other therapeutic methods are studied. NSAIDs and statins are useful in the prevention of the disease but they are failed in symptomatic treatment. There are promising studies in few patients using nerve growth factor therapy and some studies proved that peroxisome proliferator activated receptor (PPAR) agonist rosiglitazone (which is used to the treat diabetes mellitus) is effective in AD. The presently modest therapeutic interventions of AD will explode in the near future and together with the improved diagnostics of the disease they will cause further specialization with increased treatment and caring costs amplified by the ever growing number of the patients. This means that AD is and will be one of the most important diseases for the health care systems.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Nootrópicos/uso terapéutico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/prevención & control , Vacunas contra el Alzheimer/administración & dosificación , Vacunas contra el Alzheimer/efectos adversos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Péptidos beta-Amiloides/efectos adversos , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Cognición/efectos de los fármacos , Dopaminérgicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Indoles/uso terapéutico , Memantina/uso terapéutico , Ovillos Neurofibrilares/metabolismo , Índice de Severidad de la Enfermedad , Proteínas tau/metabolismoAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Vacunas contra el Alzheimer/inmunología , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/inmunología , Animales , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Perros , Evaluación Preclínica de Medicamentos , HumanosRESUMEN
The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer's disease. Recent clinical trials based on this hypothesis have been inconclusive. In this article I review the current status of the hypothesis and suggest that a major scientific need is to understand the normal function of amyloid-beta precursor protein (APP) and think how this may relate to the cell death in the disease process.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Enfermedad de Alzheimer/metabolismo , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/inmunología , Encéfalo/metabolismo , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/metabolismo , Arterias Cerebrales/fisiopatología , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Progresión de la Enfermedad , Humanos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/fisiopatologíaRESUMEN
In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Abeta vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Abeta(1-42) plus adjuvant (so-called "active" Abeta immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to Abeta and histological evidence of clearance of the hallmark AD pathology, beta-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active Abeta immunotherapy approach. This review focuses on alternative approaches to active Abeta vaccination that are currently in various stages of development - from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Vacunas contra el Alzheimer/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Inmunoterapia Activa/métodos , Inmunoterapia Activa/tendencias , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/efectos adversos , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Animales , Ensayos Clínicos como Asunto/tendencias , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/tendencias , Humanos , Meningitis Aséptica/inducido químicamente , Meningitis Aséptica/inmunología , Ratones , Fragmentos de Péptidos/efectos adversos , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Placa Amiloide/efectos de los fármacos , Placa Amiloide/inmunología , Placa Amiloide/patologíaRESUMEN
Amyloid-beta (Abeta) immunotherapy has received considerable attention as a promising approach for reducing the level of Abeta in the CNS of Alzheimer's disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with Abeta(42) developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients that received the vaccine. Generated antibodies reduced beta-amyloid deposits in the parenchyma of patients' brains, but no reduction in soluble Abeta or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of Abeta is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric Abeta, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for Abeta immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-Abeta antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Vacunas contra el Alzheimer/efectos adversos , Péptidos beta-Amiloides/antagonistas & inhibidores , Inmunoterapia Activa/métodos , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Vacunas contra el Alzheimer/genética , Vacunas contra el Alzheimer/inmunología , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Ensayos Clínicos como Asunto/estadística & datos numéricos , ADN/genética , ADN/inmunología , Epítopos/genética , Epítopos/inmunología , Humanos , Inmunoterapia Activa/efectos adversos , Inmunoterapia Activa/tendencias , Péptidos/inmunología , Péptidos/farmacología , Resultado del TratamientoRESUMEN
Alzheimer's disease (AD) is a critical health care problem that has considerable social and economic impact on society. Effective treatments have been elusive. One major causal factor for the disease is believed to be the deposition of amyloid fibrils in the brain, which ultimately leads to neurodegeneration and cognitive dysfunction. Based on the amyloid hypothesis of Alzheimer's disease, many therapies presently target the amyloid beta (Abeta) peptide, the monomeric protein fragment that assembles to form fibrils. This video article takes the form of a debate between Dr. Morgan and Dr. Landreth on the merits and drawbacks of an Alzheimer's disease vaccine. Click on Supplemental Material to watch the streaming video.