Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen

Disclosures

Expert Rev Neurother. 2011;11(9):1325-1339. 

In This Article

Graft-induced Dyskinesias

This failure of CRT to show clear benefit in the primary outcome parameters in the double-blind studies was disappointing. In itself, this would have been discouraging, but of greater concern was the description of the development of significant graft-induced dyskinesias (GIDs). GIDs are involuntary movements – dyskinesias – that occur in the absence of medication, but in the presence of the graft. Freed et al. reported GIDs in 15% of the transplanted patients more than 1-year post-transplant. Several of these patients required further surgical intervention with subthalamic DBS to relieve them of these troublesome GIDs.[130] A PET study showed DA hotspots, especially in patients developing GID.[127] Although these hotspots were not described in the PET results from longer follow-up times,[127] the mode of cell preparation and graft implantation procedure by Freed et al. was speculated to contribute to the development of GIDs.

However, the second placebo-controlled study by Olanow et al. also reported the development of significant 'off-medication' GIDs in 56.5% of the grafted patients 6–12 months after transplantation.[128] These GIDs typically consisted of stereotypic, rhythmic movements of one or both lower extremities, with three patients requiring further surgical intervention to reduce their severity.

Importantly, GIDs were only described in patients who previously suffered from L-DOPA-induced dyskinesias, yet without correlation to their severity.[125] Animal studies also demonstrated that L-DOPA priming is required for GIDs.[125]

Several theories from different laboratories around the globe are trying to explain the causes of GID. Several mechanisms have been proposed; however, the pathogenesis of this type of dyskinesia remains unclear and there is no effective way to avoid this complication, nor an effective simple treatment.

The first theory of the origin of GID was that it stemmed from imbalanced DA innervation. It has been suggested that GIDs developed as a result of fiber outgrowth from the graft, causing increased DA release[29] or as a result of imbalanced DA reinnervation.[131,132] Ma et al. reported follow-up and imaging results on five transplanted patients with GID who were no longer taking DA medications.[127] In this study, these subjects all belonged to the young subgroup of transplant recipients and had greater clinical improvement and putamen F-DOPA uptake at 1 and 2 years than those who did not develop GID. However, Hagell et al. reported no differences in either regional or global levels of striatal DA reinnervation between transplanted PD patients that presented GID to those that did not develop GIDs.[133] Another study reported that no correlation was found between the presence of GID and an excessive DA reinnervation.[128] Other theories obtained from animal models proposed that GIDs could occur as a failure of the graft to restore DA synaptic contacts with the host striatal neurons, resulting in abnormal signaling and synaptic plasticity.[134] Immunological implications have also been proposed in which inflammatory responses are triggered against the graft.[128] This is in line with the clinical observation that GIDs occurred after early discontinuation of immunosuppressive therapy, with signs of inflammatory reactions around the graft, as seen in autopsied subjects.[128,135] As stated by Politis et al., an immunological reaction around the graft may cause a degree of tissue rejection, reducing the restoration of striatal synaptic DA levels, which can be related to GIDs.[132]

Another theory is that GIDs are the consequence of serotonergic (5-HT) neurons cografted in these transplants and engage in nonphysiological properties, such as false transmitter release. Serotonergic neurons are present in the developmental stages of the VM, and therefore they are also transplanted with the graft. Since 5-HT neurons are physiologically able to store and release DA, GIDs can occur as a result of DA level mishandling. The hypothesis proposes that 5-HT neurons are responsible for dysregulating the DA release in the synapse, as a result of graft-derived excess of 5-HT neurons interacting with the normal DA neurons.[132,136]

Using in vivo brain imaging, Politis et al. showed excessive serotonergic innervation in the grafted striatum of two patients with PD who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue, but had later developed off-medication dyskinesias.[136] Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons.[136] These results indicate that GIDs were caused by the dense serotonergic innervation engaging in false transmitter release. Finally, another theory claims that PD patients that previously suffered from dyskinesias are more prone to develop GID owing to a priming effect.

Graft-induced dyskinesia presents a major problem in CRT for PD since this is a critical side effect that necessitated further surgeries in some of the patients. Moreover, it may limit the amount of cells that could be transplanted. Possible solutions to the problem include using tissue free of other cell types (such as serotonergic neurons) or only selecting patients for grafting who do not suffer from dyskinesias.

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