A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies

Patrick Aebischer, Aurélien Lathuilière, Vanessa Laversenne, Bernard Schneider, Marco Stampanoni
Oxford Univ Press, 2016
Article

Résumé

Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-beta peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-beta antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-beta antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 A mu g/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-beta antibodies dramatically reduces amyloid-beta(40) and amyloid-beta(42) levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Official source

https://infoscience.epfl.ch/record/219730?ln=fr

À propos de ce résultat

Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Concepts associés

Chargement

Publications associées

Chargement

Patrick Aebischer, Aurélien Lathuilière, Vanessa Laversenne, Bernard Schneider, Marco Stampanoni
Oxford Univ Press, 2016
Article

Résumé

Official source

https://infoscience.epfl.ch/record/219730?ln=fr

À propos de ce résultat

Concepts associés (5)

Concepts associés

Chargement

Publications associées (3)

Publications associées

Chargement

Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. As populations are aging in most parts of the world, the number of people with Alzheimer’s disease is expected to dramatically increase. This devastating neurodegenerative disorder remains the only major source of mortality without any effective disease-modifying treatment. Nevertheless, the progress made in understanding underlying disease mechanisms linked to amyloid and tau pathologies, led to the development of novel therapeutic strategies. The most clinically advanced experimental treatment is based on monoclonal antibodies (passive immunization) directed against the amyloid β peptide, a critical contributor to the neuropathology of Alzheimer’s disease. Although immunotherapy is able to clear cerebral amyloid deposits in patients, it has so far failed to slow down the loss of cognitive functions. In order to potentiate therapeutic effects, it may be critical to initiate the treatment before the first cognitive symptoms, and therefore chronically administer antibodies over years, possibly decades. This prompts the development of alternative strategies for the long-term delivery of therapeutic antibodies. To address this question, we have investigated an innovative approach based on a biologically active subcutaneous device encapsulating cells genetically engineered for the production of recombinant antibodies. In order to demonstrate that encapsulated cell technology can achieve peripheral continuous delivery of antibodies and lead to significant antibody exposure inside the brain, we rationally optimized parameters that are crucial to the rate of antibody secretion from such a cellular implant. In the first part of the thesis, we explored the utilization of lentiviral vectors for the genetic engineering of antibody secreting cell lines. We developed a dual vector strategy to significantly improve the efficiency of stable cell line generation. Moreover, the lentiviral transduction of C2C12 murine myoblasts allowed for the isolation of individual clones demonstrating high cell specific productivity, thus validating the use of C2C12 as a preclinical surrogate cell line for allogeneic implantation in disease mouse models. In the second part of the present work, we engineered a novel cell encapsulation device specially designed for subcutaneous implantation.We implemented a highly reproducible and scalable process to assemble devices supporting the implantation of large quantities of cells. Moreover, the in vivo optimization of initial cell seeding parameters enabled encapsulated cells to survive for months at high density inside the device. The final part of the present work assessed therapeutic efficacy of the newly developed cell encapsulation system for peripheral immunization against brain amyloid pathology. Devices secreting anti-Aβ antibodies were subcutaneously implanted in two transgenic mouse models of Alzheimer’s disease. Antibody levels in the mouse plasma reached 40 μg/ ml for several months, demonstrating long-term implant efficacy. Furthermore, we could demonstrate immunodecoration of amyloid plaques inside the brain with the delivered antibody, demonstrating penetration into the central nervous system. Remarkably, in the two mouse models of Alzheimer’s disease, brain amyloidosis was significantly reduced in the treated animals. Overall, this thesis work shows that peripheral implantation of encapsulated antibody-secreting myoblast cells is an effective strategy for passive immunization, particularly in the challenging context of delivering therapeutic amounts of antibodies to the central nervous system. Indeed, we demonstrate that anti-Aβ antibodies administered by subcutaneous bioactive implants can significantly decrease amyloid burden in mouse models of Alzheimer’s neuropathology.

EPFL2013

Chargement

Transmission and spreading of tauopathy in transgenic mouse brain

Tristan Bolmont

Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease(1). In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex(2). Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular beta-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of beta-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases(1). Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia(3-5). Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein(6,8). By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration(7,8). Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.

Nature Publishing Group2009

Chargement

Application of anti-amyloid beta immunization using encapsulated cell technology in mouse models of Alzheimer's disease

Vanessa Laversenne

Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD is characterized by the deposition of two aggregated proteins: Amyloid beta (Aß) and hyperphosphorylated tau. Accumulations of these proteins are thought to be the signature of a pathogenic process causing the loss of neurons and synaptic connections associated with severe cognitive impairments in AD patients. Other important factors are involved in the neurodegeneration occurring in AD, such as neuroinflammation. In the present thesis work, we are investigating the effects of passive anti-Aß immunization. Passive anti-Aß immunization consists in the delivery of antibodies targeting Aß, with the aim to prevent its accumulation and promote the removal of pathological amyloid species. Although the treatment has been shown to clear amyloid pathology in the brain of AD patients, it has so far failed to prevent or slow down cognitive decline. Hence, it is important to determine the effects of anti-Aß immunization when administered either before or during Aß deposition, and explore how the treatment affects the Alzheimerâs manifestations in mouse models combining Aß and tau pathologies. In order to continuously deliver antibodies in AD mouse models, we used encapsulated cell technology (ECT) to implant myoblasts genetically engineered and secrete the recombinant mAb11 mouse IgG2a antibody directed against aggregated forms of Aß. Using this approach, we investigated the following three topics of research:

We examined the effect of a preventive administration of anti-Aß antibodies in a slowly progressing mouse model with both Aß and tau (P301L) pathologies. We demonstrated that delivery of anti-Aß antibodies before the onset of the disease dramatically reduces Aß pathology. We also found that the treatment decreases hyperphosphorylated tau accumulation and recruits microglial around Aß plaques.
We next assessed the effects of passive anti-Aß immunization in another AD mouse model overexpressing both Aß and wild-type (WT) tau. In this second study, we administered the anti-Aß antibodies when both Aß and tau pathologies were already established. In the hippocampal formation, we showed that WT tau overexpression might affect the microglial response to ongoing pathology by reducing the tight interaction of these cells with the amyloid plaques. This effect, however, is counteracted by passive anti-Aß immunization, which was found to redirect microglia towards Aß deposits. In addition, passive anti-Aß immunization decreases tau spreading throughout the hippocampus, but fails to prevent neither tau phosphorylation, nor the hippocampal degeneration induced by local tau overexpression.
In parallel, we developed a human myoblast cell line secreting anti-Aß antibodies for translation of our ECT towards human application. Using C2C12 mouse myoblasts, our flat-sheet device allowed for long-term continuous antibody delivery in the plasma of subcutaneously implanted mice. We were able to generate antibody-secreting human cells using the immortalized C25 cell It was possible to differentiate these cells into myotubes and adapt them to long-term survival inside the capsules maintained in vitro. However, when implanted in the subcutaneous tissue of immunocompromised mice, myoblasts survived in the ECT device as a thin layer of cells and were not able to secrete recombinant antibodies in sufficient amounts to be considered for therapeutic purpose.

EPFL2019

Chargement

EPFL2013

Application of anti-amyloid beta immunization using encapsulated cell technology in mouse models of Alzheimer's disease

Vanessa Laversenne

We examined the effect of a preventive administration of anti-Aß antibodies in a slowly progressing mouse model with both Aß and tau (P301L) pathologies. We demonstrated that delivery of anti-Aß antibodies before the onset of the disease dramatically reduces Aß pathology. We also found that the treatment decreases hyperphosphorylated tau accumulation and recruits microglial around Aß plaques.
We next assessed the effects of passive anti-Aß immunization in another AD mouse model overexpressing both Aß and wild-type (WT) tau. In this second study, we administered the anti-Aß antibodies when both Aß and tau pathologies were already established. In the hippocampal formation, we showed that WT tau overexpression might affect the microglial response to ongoing pathology by reducing the tight interaction of these cells with the amyloid plaques. This effect, however, is counteracted by passive anti-Aß immunization, which was found to redirect microglia towards Aß deposits. In addition, passive anti-Aß immunization decreases tau spreading throughout the hippocampus, but fails to prevent neither tau phosphorylation, nor the hippocampal degeneration induced by local tau overexpression.
In parallel, we developed a human myoblast cell line secreting anti-Aß antibodies for translation of our ECT towards human application. Using C2C12 mouse myoblasts, our flat-sheet device allowed for long-term continuous antibody delivery in the plasma of subcutaneously implanted mice. We were able to generate antibody-secreting human cells using the immortalized C25 cell It was possible to differentiate these cells into myotubes and adapt them to long-term survival inside the capsules maintained in vitro. However, when implanted in the subcutaneous tissue of immunocompromised mice, myoblasts survived in the ECT device as a thin layer of cells and were not able to secrete recombinant antibodies in sufficient amounts to be considered for therapeutic purpose.

EPFL2019