l-DOPA- and graft-induced dyskinesia following transplantation

Lane, Emma Louise; Winkler, Christian

doi:10.1016/b978-0-444-59575-1.00007-7

Cited by 13 publications

(8 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A major complication associated with fetal dopamine neuron grafts in clinical trials was the eventual manifestation of graft-induced dyskinesias in a subset of patients (Lane and Winkler, 2012). In some patients, the graft-induced-dyskinesias were sufficiently severe that they required a second brain surgery, deep brain stimulation, to control the sporadic movements.…”

Section: Discussionmentioning

confidence: 99%

Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

et al. 2017

View full text Add to dashboard Cite

SummaryA major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

show abstract

Section: Discussionmentioning

confidence: 99%

Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Therefore, in some cases it was not immediately apparent that the involuntary movements actually remained after temporary cessation of L‐dopa medication and thereby were GIDs by definition. Following a decade of research in animal models of GIDs we now have a better understanding of when and why GIDs develop [11]. As described in more detail in the section below devoted to TRANSEURO, researchers today believe that GIDs can be minimized or avoided in future trials.…”

Section: Cell Replacement Therapy Results So Farmentioning

confidence: 99%

Review: The future of cell therapies and brain repair: Parkinson's disease leads the way

Petit

Olsson

Brundin

2014

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini‐review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof‐of‐principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α‐synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union‐funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease.

show abstract

“…First, 15% to 56% of transplant recipients developed a novel form of aberrant motor behavior classified as graft‐induced dyskinesia (GID) . This topic is beyond the scope of the present discussion, but is covered in several reviews . Second, blinded, controlled clinical trials revealed substantial variability in the clinical response to transplantation.…”

Section: What We Knowmentioning

confidence: 95%

“…17,18 This topic is beyond the scope of the present discussion, but is covered in several reviews. 20,21 Second, blinded, controlled clinical trials revealed substantial variability in the clinical response to transplantation. The two trials funded by the National Institutes of Health failed to achieve their primary endpoints, but drew secondary conclusions: (1) Older individuals experienced less benefit than younger individuals 17 ; 2) individuals with more severe disease benefited less than those with milder disease.…”

Section: Dopamine Neuron Grafts In Persons With Pdmentioning

confidence: 99%

Cell therapy for Parkinson's disease: Why it doesn't work every time

et al. 2019

View full text Add to dashboard Cite

The clinical experience with cell replacement therapy for advanced PD has yielded notable successes and failures. A recent autopsy case report of an individual that received implants of fetal dopamine neurons 16 years previously, but at no time experienced clinical benefit despite the best documented survival of grafted neurons and most extensive reinnervation of the striatum, raises sobering issues. With good reason, a great deal of effort in cell replacement science continues to focus on optimizing the cell source and implantation procedure. Here, we describe our preclinical studies in aged rats indicating that despite survival of large numbers of transplanted dopamine neurons and dense reinnervation of the striatum, synaptic connections between graft and host are markedly decreased and behavioral recovery is impaired. This leads us to the hypothesis that the variability in therapeutic response to dopamine neuron grafts may be less about the viability of transplanted neurons and more about the integrity of the aged, dopamine‐depleted striatum and its capacity for repair. Replacement of dopamine innervation only can be fully effective if the correct target is present. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

show abstract

l-DOPA- and graft-induced dyskinesia following transplantation

Cited by 13 publications

References 99 publications

Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

Review: The future of cell therapies and brain repair: Parkinson's disease leads the way

Cell therapy for Parkinson's disease: Why it doesn't work every time

Contact Info

Product

Resources

About