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Human Embryonic Stem Cell-Derived Dopaminergic Grafts Alleviate L-DOPA Induced Dyskinesia

Elabi, Osama F LU ; Pass, Rachel ; Sormonta, Irene ; Nolbrant, Sara LU ; Drummond, Nicola ; Kirkeby, Agnete LU ; Kunath, Tilo ; Parmar, Malin LU orcid and Lane, Emma L LU (2022) In Journal of Parkinson's Disease 12(6). p.1881-1896
Abstract

BACKGROUND: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson's disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft.

OBJECTIVE: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons.

METHODS: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for 18 weeks following surgical implantation of... (More)

BACKGROUND: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson's disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft.

OBJECTIVE: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons.

METHODS: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for 18 weeks following surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories.

RESULTS: Grafts from both protocols elicited reduction in amphetamine-induced rotations. Reduced L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) or dopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons.

CONCLUSION: Critically, we found that L-DOPA was not detrimental to graft function, potentially enhancing graft maturation and promoting an A9 phenotype. Early improvement of L-DOPA-induced dyskinesia suggests that grafts may support the handling of exogenously supplied dopamine earlier than improvements in amphetamine-induced behaviours indicate. Given that one of the protocols will be employed in the production of cells for the European STEM-PD clinical trial, this is vital information for the management of patients and achieving optimal outcomes following transplantation of hESC-derived grafts for PD.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
L-dopa-induced dyskinesia, 6-OHDA lesioned rat, Parkinson’s disease, abnormal involuntary movements, transplantation, human embryonic stem cells
in
Journal of Parkinson's Disease
volume
12
issue
6
pages
16 pages
publisher
IOS Press
external identifiers
  • pmid:35466951
  • scopus:85137158954
ISSN
1877-718X
DOI
10.3233/JPD-212920
language
English
LU publication?
yes
id
6f5110a7-74c5-42ee-918d-359308a0882f
date added to LUP
2022-05-20 14:20:47
date last changed
2024-06-12 08:08:03
@article{6f5110a7-74c5-42ee-918d-359308a0882f,
  abstract     = {{<p>BACKGROUND: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson's disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft.</p><p>OBJECTIVE: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons.</p><p>METHODS: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for 18 weeks following surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories.</p><p>RESULTS: Grafts from both protocols elicited reduction in amphetamine-induced rotations. Reduced L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) or dopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons.</p><p>CONCLUSION: Critically, we found that L-DOPA was not detrimental to graft function, potentially enhancing graft maturation and promoting an A9 phenotype. Early improvement of L-DOPA-induced dyskinesia suggests that grafts may support the handling of exogenously supplied dopamine earlier than improvements in amphetamine-induced behaviours indicate. Given that one of the protocols will be employed in the production of cells for the European STEM-PD clinical trial, this is vital information for the management of patients and achieving optimal outcomes following transplantation of hESC-derived grafts for PD.</p>}},
  author       = {{Elabi, Osama F and Pass, Rachel and Sormonta, Irene and Nolbrant, Sara and Drummond, Nicola and Kirkeby, Agnete and Kunath, Tilo and Parmar, Malin and Lane, Emma L}},
  issn         = {{1877-718X}},
  keywords     = {{L-dopa-induced dyskinesia; 6-OHDA lesioned rat; Parkinson’s disease; abnormal involuntary movements; transplantation; human embryonic stem cells}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{6}},
  pages        = {{1881--1896}},
  publisher    = {{IOS Press}},
  series       = {{Journal of Parkinson's Disease}},
  title        = {{Human Embryonic Stem Cell-Derived Dopaminergic Grafts Alleviate L-DOPA Induced Dyskinesia}},
  url          = {{http://dx.doi.org/10.3233/JPD-212920}},
  doi          = {{10.3233/JPD-212920}},
  volume       = {{12}},
  year         = {{2022}},
}