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Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. In vivo studies demonstrated...

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Autores principales: Wahlberg, Lars U., Emerich, Dwaine F., Kordower, Jeffrey H., Bell, William, Fradet, Tracie, Paolone, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663965/
https://www.ncbi.nlm.nih.gov/pubmed/34909639
http://dx.doi.org/10.1016/j.crphar.2020.04.001
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author Wahlberg, Lars U.
Emerich, Dwaine F.
Kordower, Jeffrey H.
Bell, William
Fradet, Tracie
Paolone, Giovanna
author_facet Wahlberg, Lars U.
Emerich, Dwaine F.
Kordower, Jeffrey H.
Bell, William
Fradet, Tracie
Paolone, Giovanna
author_sort Wahlberg, Lars U.
collection PubMed
description Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. In vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease.
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spelling pubmed-86639652021-12-13 Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain Wahlberg, Lars U. Emerich, Dwaine F. Kordower, Jeffrey H. Bell, William Fradet, Tracie Paolone, Giovanna Curr Res Pharmacol Drug Discov Article Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. In vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease. Elsevier 2020-05-06 /pmc/articles/PMC8663965/ /pubmed/34909639 http://dx.doi.org/10.1016/j.crphar.2020.04.001 Text en © 2020 Published by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Wahlberg, Lars U.
Emerich, Dwaine F.
Kordower, Jeffrey H.
Bell, William
Fradet, Tracie
Paolone, Giovanna
Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain
title Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain
title_full Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain
title_fullStr Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain
title_full_unstemmed Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain
title_short Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain
title_sort long-term, stable, targeted biodelivery and efficacy of gdnf from encapsulated cells in the rat and goettingen miniature pig brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663965/
https://www.ncbi.nlm.nih.gov/pubmed/34909639
http://dx.doi.org/10.1016/j.crphar.2020.04.001
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