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

Abstract

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.

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease

“…Indeed, despite the significant scientific advancement of the last decades, the causes, mechanisms and determinant factors leading to DAergic neuron demise in PD still remain poorly understood [24]. Over the years, numerous novel therapies are being suggested along with development of medications to treat various non-motor symptoms to improve quality of life of patients, and excellent reviews have recently discussed these topics elsewhere [15,[25][26][27].…”

Cellular transplantation for Parkinson’s disease: a strategy whose time has passed

“…During development, embryonic dopaminergic neurons migrate from the nigra to the striatum and make meaningful connections in a completely different microenvironment (i.e., the unmyelinated embryonic brain) than the one receiving a transplant (aged, fully myelinated, and, again, hostile to dopaminergic neurons). A recent review by Collier et al 39 highlights this obstacle, demonstrating that grafting is far more successful in the young mammalian brain than in the aged one. In the conclusion of their paper they state, "It is unreasonable to expect that a striatum structurally altered by aging, [dopamine (DA)] depletion, and genetic factors that may predispose to impaired plasticity, perhaps irreversibly, can support appropriate integration of new DA input, uniformly producing therapeutic benefit."…”

Oxygen-glucose deprivation in neurons: implications for cell transplantation therapies

“…Long-term follow-up of early clinical trials proved the concept that replacing lost dopamine neurons with neuronal progenitors derived from fetal ventral mesencephalon (VM) (the region of the developing brain in which the dopamine projection neurons are born) can provide remarkable recovery in a subset of PD patients [6,7]. The many practical and ethical difficulties inherent to working with fetal tissue has led to a concerted effort across multiple labs to generate stem cellderived sources of dopamine donor neurons [8], although studies with fetal-derived progenitors continue to be important for understanding factors that influence the reliability and robustness of cell replacement therapy in PD, thus paving the way for future stem cell-based strategies [9] [10].…”