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2.
Nature ; 537(7618): 50-6, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27582220

RESUMEN

Alzheimer's disease (AD) is characterized by deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aß to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aß. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aß, and reduce soluble and insoluble Aß in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aß in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/efectos de los fármacos , Amiloide/metabolismo , Péptidos beta-Amiloides/química , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ensayos Clínicos Fase III como Asunto , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Modelos Biológicos , Placa Amiloide/patología , Agregación Patológica de Proteínas/tratamiento farmacológico , Solubilidad
3.
Artículo en Inglés | MEDLINE | ID: mdl-33468560

RESUMEN

OBJECTIVE: To test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS. METHODS: In rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36). RESULTS: In rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8+ T cells. In a multivariate regression analysis, the absolute lymphocyte count (ALC) was associated with age at therapy start, baseline ALC, and DMF/MEF dosage but not with previous immunosuppressive medication and sex. Furthermore, the ALC increased in a small cohort of patients with MS (n = 6/7) after switching from DMF/MEF to DMF monotherapy. CONCLUSIONS: Fumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF.


Asunto(s)
Dimetilfumarato/química , Dimetilfumarato/farmacología , Fumaratos/química , Fumaratos/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Animales , Estudios Transversales , Dimetilfumarato/uso terapéutico , Femenino , Fumaratos/uso terapéutico , Perfilación de la Expresión Génica/métodos , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/sangre , Esclerosis Múltiple/genética , Ratas , Ratas Sprague-Dawley , Estudios Retrospectivos
4.
Sci Rep ; 7: 42054, 2017 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-28181536

RESUMEN

Dimethyl fumarate (DMF) is indicated for the treatment of relapsing multiple sclerosis and may exert therapeutic effects via activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway. Following oral DMF administration, central nervous system (CNS) tissue is predominantly exposed to monomethyl fumarate (MMF), the bioactive metabolite of DMF, which can stabilize NRF2 and induce antioxidant gene expression; however, the detailed NRF2-dependent mechanisms modulated by MMF that lead to cytoprotection are unknown. Our data identify a mechanism for MMF-mediated cytoprotection in human astrocytes that functions in an OSGIN1-dependent manner, specifically via upregulation of the OSGIN1-61 kDa isoform. NRF2-dependent OSGIN1 expression induced P53 nuclear translocation following MMF administration, leading to cell-cycle inhibition and cell protection against oxidative challenge. This study provides mechanistic insight into MMF-mediated cytoprotection via NRF2, OSGIN1, and P53 in human CNS-derived cells and contributes to our understanding of how DMF may act clinically to ameliorate pathological processes in neurodegenerative disease.


Asunto(s)
Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Citoprotección , Fumaratos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas/metabolismo , Proteínas Reguladoras de la Apoptosis , Células Cultivadas , Humanos
5.
Antioxid Redox Signal ; 24(18): 1058-71, 2016 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-26980071

RESUMEN

AIMS: Gastro-resistant dimethyl fumarate (DMF) is an oral therapeutic indicated for the treatment of relapsing multiple sclerosis. Recent data suggest that a primary pharmacodynamic response to DMF treatment is activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway; however, the gene targets modulated downstream of NRF2 that contribute to DMF-dependent effects are poorly understood. RESULTS: Using wild-type and NRF2 knockout mice, we characterized DMF transcriptional responses throughout the brain and periphery to understand DMF effects in vivo and to explore the necessity of NRF2 in this process. Our findings identified tissue-specific expression of NRF2 target genes as well as NRF2-dependent and -independent gene regulation after DMF administration. Furthermore, using gene ontology, we identified common biological pathways that may be regulated by DMF and contribute to in vivo functional effects. INNOVATION: Together, these data suggest that DMF modulates transcription through multiple pathways, which has implications for the cytoprotective, immunomodulatory, and clinical properties of DMF. CONCLUSION: These findings provide further understanding of the DMF mechanism of action and propose potential therapeutic targets that warrant further investigation for treating neurodegenerative diseases. Antioxid. Redox Signal. 24, 1058-1071.


Asunto(s)
Antiinflamatorios/farmacocinética , Dimetilfumarato/farmacocinética , Factor 2 Relacionado con NF-E2/metabolismo , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dimetilfumarato/administración & dosificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de Órganos , Distribución Tisular , Transcriptoma/efectos de los fármacos
6.
Neuropharmacology ; 103: 57-68, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26690893

RESUMEN

Reducing the production of larger aggregation-prone amyloid ß-peptides (Aß) remains an untested therapeutic approach for reducing the appearance and growth of Aß plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aß peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aß42, increased the levels of Aß38 and had little effect on the levels of Aß40, the most abundant Aß species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aß42 levels and Aß plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aß42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease.


Asunto(s)
Aldehídos/farmacocinética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Aldehídos/administración & dosificación , Péptidos beta-Amiloides/sangre , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Macaca fascicularis , Masculino , Ratones , Placa Amiloide/metabolismo , Isoformas de Proteínas/sangre , Ratas , Ratas Endogámicas F344
7.
PLoS One ; 10(3): e0120254, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25793262

RESUMEN

Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration-dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology.


Asunto(s)
Dimetilfumarato/farmacología , Fumaratos/farmacología , Glutatión/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Cisteína/metabolismo , Dimetilfumarato/química , Espacio Extracelular/metabolismo , Fumaratos/química , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2/genética , Transporte de Proteínas/efectos de los fármacos
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