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Journal article

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

  • Lathuilière A Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland patrick.aebischer@epfl.ch bernard.schneider@epfl.ch bernd.bohrmann@roche.com.
  • Laversenne V Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
  • Astolfo A Swiss Light Source, Paul Scherrer Institute (PSI), 5232, Villigen-PSI, Switzerland.
  • Kopetzki E Pharma Research and Early Development, DTA Neuroscience, Roche Innovation Center Penzberg, F. Hoffmann-La Roche, Switzerland.
  • Jacobsen H Pharma Research and Early Development, DTA Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche, Switzerland.
  • Stampanoni M Swiss Light Source, Paul Scherrer Institute (PSI), 5232, Villigen-PSI, Switzerland.
  • Bohrmann B Pharma Research and Early Development, DTA Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche, Switzerland.
  • Schneider BL Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
  • Aebischer P Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
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  • 2016-03-10
Published in:
  • Brain : a journal of neurology. - 2016
Alzheimer’s disease
antibody
cellular implant
encapsulation
immunization
Alzheimer Disease
Amyloid beta-Peptides
Animals
Antibodies, Monoclonal
Brain
Cells, Cultured
Drug Implants
Immunization, Passive
Mice
Mice, Transgenic
Neuroprotection
Peptide Fragments
Plaque, Amyloid
Recombinant Proteins
Subcutaneous Absorption
Tauopathies
English 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-β 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-β 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-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/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-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 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.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/278319
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