Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App

Animals Mice Alzheimer Disease / therapy Amyloid beta-Peptides Brain-Derived Neurotrophic Factor / therapeutic use Feasibility Studies Drug Delivery Systems / methods
Alzheimer’s disease (AD) App NL−G−F knock-in mice Brain-derived neurotrophic factor (BDNF) Drug delivery Encapsulated cell biodelivery (ECB) Therapy

Journal

Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643

Informations de publication

Date de publication:
18 08 2023
Historique:
received: 30 01 2023
accepted: 29 07 2023
medline: 21 8 2023
pubmed: 19 8 2023
entrez: 18 8 2023
Statut: epublish

Résumé

Alzheimer's disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (App ECB's containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old App The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery. The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies.

Sections du résumé

BACKGROUND
Alzheimer's disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (App
METHODS
ECB's containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old App
RESULTS
The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery.
CONCLUSIONS
The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies.

Identifiants

DOI: 10.1186/s13195-023-01282-x PMID: 37596686 PMC: PMC10436657
pubmed: 37596686
doi: 10.1186/s13195-023-01282-x
pii: 10.1186/s13195-023-01282-x
pmc: PMC10436657
doi:

Substances chimiques

Amyloid beta-Peptides 0
Brain-Derived Neurotrophic Factor 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

137

Informations de copyright

© 2023. BioMed Central Ltd., part of Springer Nature.

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Auteurs

Simone Tambaro (S)

Department of Neurobiology, Care Sciences and Society; Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Sumonto Mitra (S)

Department of Neurobiology, Care Sciences and Society; Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden. sumonto.mitra@ki.se.

Ruchi Gera (R)

Department of Neurobiology, Care Sciences and Society; Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.

Bengt Linderoth (B)

Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institutet, Stockholm, Sweden.

Lars U Wahlberg (LU)

Gloriana Therapeutics, Inc., Warren, RI, USA.
Sinfonia Biotherapeutics AB, Huddinge, Sweden.

Taher Darreh-Shori (T)

Department of Neurobiology, Care Sciences and Society; Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.

Homira Behbahani (H)

Department of Neurobiology, Care Sciences and Society; Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.

Per Nilsson (P)

Department of Neurobiology, Care Sciences and Society; Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Maria Eriksdotter (M)

Department of Neurobiology, Care Sciences and Society; Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
Theme Inflammation and Aging, Karolinska University Hospital, Huddinge, Sweden.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Feasibility and therapeutical potential of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Feasibility and therapeutical potential of...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Feasibility and therapeutical potential of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › Feasibility and therapeutical potential of...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Facteurs de croissance nerveuse › Facteur neurotrophique dérivé du cerveau › Feasibility and therapeutical potential of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études de faisabilité › Feasibility and therapeutical potential of...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Systèmes de délivrance de médicaments › Feasibility and therapeutical potential of...