Human embryonic stem cell-derived dopaminergic grafts alleviate L-DOPA induced dyskinesia

Osama F. Elabi, Rachel Pass, Irene Sormonta, Sara Nolbrant, Nicola Drummond, Agnete Kirkeby, Tilo Kunath, Malin Parmar, Emma L. Lane

Research output: Contribution to journalArticlepeer-review

Abstract

First-in-human studies to test the efficacy and safety of using 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 of PD have indicated that the benefits could be akin to those shown with foetal tissue, but have thus far failed to consider how ongoing L-DOPA administration might impact on graft survival, differentiation or function. Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA for 4 weeks prior to surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories. Daily administration of saline or L-DOPA continued for 18 weeks, along with cyclosporine immunosuppression. Grafts from both protocols elicited reduction in amphetamine-induced rotations. A significant reduction in L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) ordopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons. Critically, we found that L-DOPA was not detrimental to graft function, that it in fact may enhance graft maturation and promote the A9 phenotype. The early improvement of LDOPA-induced dyskinesia may indicate that grafts are able to support the handling of exogenously supplied dopamine earlier than indicated by improvements in amphetamine-induced behaviours. 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 human ESC-derived grafts for Parkinson’s disease.
Original languageEnglish
Pages (from-to)1-16
Number of pages17
JournalJournal of Parkinson's disease
DOIs
Publication statusPublished - 22 Apr 2022

Keywords

  • L-dopa-induced dyskinesia
  • 6-OHDA lesioned rat
  • Parkinson’s disease
  • abnormal involuntary movements
  • transplantation
  • human embryonic stem cells

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