Role of Cell Therapy in Parkinson Disease
Role of Cell Therapy in Parkinson Disease
Clinical studies involving intrastriatal transplantation of embryonic mesencephalic tissue in patients with Parkinson disease (PD) have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine release and movement-related frontal cortical activation, and produce significant symptomatic relief. In the most successful cases, patients have been able to withdraw from levodopa treatment after undergoing transplantation and resume an independent life. There are, however, several problems linked to the use of primary embryonic tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients; 2) variability of functional outcome (major improvement in some and modest if any clinical benefit in others); and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in the treatment of PD. For the development of a clinically useful cell therapy we need to define better criteria for patient selection and how graft placement should be optimized in each individual. Most importantly, we need to generate large numbers of viable dopamine neurons in preparations that are standardized and quality controlled. Stem cells could be useful as an unlimited source of dopamine neurons. Thus far, neurons with at least some dopaminergic characteristics have been generated from stem cells. In most cases, however, their survival after grafting in animals has been poor, and it is also unclear if they function as normal dopamine neurons. Several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.
The cell replacement strategy in PD has been based on the idea that neural graft-induced restoration of dopamine neurotransmission in the striatum, even if the disease is chronic and also affects other neuronal systems and brain regions, could lead to substantial and long-lasting functional recovery. It was demonstrated more than 20 years ago that embryonic mesencephalic dopamine-rich tissue implanted in a rat model of PD reinnervated the denervated striatum and ameliorated some functional deficits. Extensive animal studies subsequently showed that the grafted dopamine neurons display many of the morphological and functional characteristics of intrinsic dopamine neurons; that is, they reinnervate the denervated striatum and form synaptic contacts with host neurons, are spontaneously active and release dopamine, and receive afferent input from the host. The graft-induced reinnervation is accompanied by significant amelioration of several but not all aspects of the dopamine deficiency syndrome both in rodents and monkeys. Clinical trials involving transplantation of human embryonic mesencephalic tissue to the striatum in patients with PD were initiated in 1987. At that time the efficacy of cell replacement in the diseased human brain was unknown. In many of the scientific efforts during the past 15 years the main objective has been to provide proof-of-principle that: 1) the grafted dopamine neurons can survive and form connections in the brains of PD patients; 2) the patient's brain can integrate and use the grafted neurons; and 3) the grafts can induce a measurable clinical improvement. Most clinical studies have been performed as open-label trials in relatively small groups of patients. Two double-blinded randomized clinical trials, however, were initiated in the mid-1990s to evaluate the effectiveness of neural grafting according to current procedures compared with that of sham surgery.
In this article, we will first argue, based on the clinical experiences with neural transplantation thus far, that cell replacement therapy can be effective in patients with PD. We will also conclude, however, that the use of primary embryonic tissue is associated with problems related to availability, standardization, variation in patient-related functional outcome, and adverse effects. In light of these factors, we will then discuss the possible role of the stem cell technology for the further development of a cell therapy in the treatment of PD.
Clinical studies involving intrastriatal transplantation of embryonic mesencephalic tissue in patients with Parkinson disease (PD) have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine release and movement-related frontal cortical activation, and produce significant symptomatic relief. In the most successful cases, patients have been able to withdraw from levodopa treatment after undergoing transplantation and resume an independent life. There are, however, several problems linked to the use of primary embryonic tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients; 2) variability of functional outcome (major improvement in some and modest if any clinical benefit in others); and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in the treatment of PD. For the development of a clinically useful cell therapy we need to define better criteria for patient selection and how graft placement should be optimized in each individual. Most importantly, we need to generate large numbers of viable dopamine neurons in preparations that are standardized and quality controlled. Stem cells could be useful as an unlimited source of dopamine neurons. Thus far, neurons with at least some dopaminergic characteristics have been generated from stem cells. In most cases, however, their survival after grafting in animals has been poor, and it is also unclear if they function as normal dopamine neurons. Several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.
The cell replacement strategy in PD has been based on the idea that neural graft-induced restoration of dopamine neurotransmission in the striatum, even if the disease is chronic and also affects other neuronal systems and brain regions, could lead to substantial and long-lasting functional recovery. It was demonstrated more than 20 years ago that embryonic mesencephalic dopamine-rich tissue implanted in a rat model of PD reinnervated the denervated striatum and ameliorated some functional deficits. Extensive animal studies subsequently showed that the grafted dopamine neurons display many of the morphological and functional characteristics of intrinsic dopamine neurons; that is, they reinnervate the denervated striatum and form synaptic contacts with host neurons, are spontaneously active and release dopamine, and receive afferent input from the host. The graft-induced reinnervation is accompanied by significant amelioration of several but not all aspects of the dopamine deficiency syndrome both in rodents and monkeys. Clinical trials involving transplantation of human embryonic mesencephalic tissue to the striatum in patients with PD were initiated in 1987. At that time the efficacy of cell replacement in the diseased human brain was unknown. In many of the scientific efforts during the past 15 years the main objective has been to provide proof-of-principle that: 1) the grafted dopamine neurons can survive and form connections in the brains of PD patients; 2) the patient's brain can integrate and use the grafted neurons; and 3) the grafts can induce a measurable clinical improvement. Most clinical studies have been performed as open-label trials in relatively small groups of patients. Two double-blinded randomized clinical trials, however, were initiated in the mid-1990s to evaluate the effectiveness of neural grafting according to current procedures compared with that of sham surgery.
In this article, we will first argue, based on the clinical experiences with neural transplantation thus far, that cell replacement therapy can be effective in patients with PD. We will also conclude, however, that the use of primary embryonic tissue is associated with problems related to availability, standardization, variation in patient-related functional outcome, and adverse effects. In light of these factors, we will then discuss the possible role of the stem cell technology for the further development of a cell therapy in the treatment of PD.
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