Cell Transplantation for the Treatment of Parkinson's Disease
Cell Transplantation for the Treatment of Parkinson's Disease
Cell transplantation is an experimental therapy for Parkinson's disease (PD) and other movement disorders. Several open-label research trials have shown clinically meaningful improvement in parkinsonian signs and symptoms after striatal transplantation of allogeneic fetal ventral mesencephalic (FVM) tissue. However, ethical concerns, variability in surgical techniques, and reports of unusual late complications in a few patients in a clinical trial have limited the use of allogeneic FVM tissue to a few research centers. Research into alternative cell sources such as porcine FVM and allogeneic retinal pigment epithelial cells has shown promising results in preclinical trials, and they are currently being tested in clinical trials. Novel strategies to improve cell survival and to avoid immune rejection of transplants show promising results in preclinical trials. This article focuses on these recent advances and compares the potential clinical utility of these emerging cell therapies for the treatment of advanced PD.
Objectives: On completion of this article, the reader will understand current concepts of cell transplantation as experimental therapy for involuntary movement disorders.
Accreditation: The Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit: The Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.
Disclosure: Statements have been obtained regarding the author's relationships with financial supporters of this activity. There is no apparent conflict of interest related to the context of participation of the author of this article. Dr. Subramanian has served as a paid consultant for Titan Pharmaceuticals, Inc., and has received research grants from Titan Pharmaceuticals, Inc. and Diacrin-Genzyme, LLC.
Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic neurons in the substantia nigra (SN). Dopaminergic neurons in the SN have their cell bodies located in a compact area on the dorsomedial aspect of the nucleus called the SN pars compacta (SNc). These neurons give rise to long axonal projections into the caudate nucleus and the putamen and make short dendritic connections to the neurons in the SN pars reticulata (SNr). The pathophysiology of PD has been attributed to the dramatic drop in dopamine content within the striatum (particularly in the postcommisural putamen) secondary to the degeneration of SNc neurons. This results in disinhibition of the subthalamic nucleus (STN), resulting in increased internal globus pallidum and SNr output. The net result is the inhibition of cortical motor neurons. Pharmacological therapeutic strategies for PD are currently centered around replacement of dopamine in the brain either by exogenous supplementation of dopamine precursors (levodopa), dopamine agonists, cathecol-O-methyltransferase (COMT) inhibitors, or drugs that modulate glutamate- or acetylcholine-mediated neurotransmission.
The discovery of levodopa, a precursor of dopamine and the most potent oral dopaminergic agent to date to ameliorate parkinsonism, revolutionized the treatment of PD in the 1960s, and it continues to be the best available treatment for PD. However, chronic intermittent treatment with levodopa leads to disabling side effects in the majority of patients with Parkinson's disease. It has been shown that continuous systemic administration (intravenous or intraduodenal) of levodopa can prevent the occurrence of these disabling side effects. However, these methods of administration are impractical and unacceptable to patients with PD. Although many attempts have been made to produce continuous-release oral preparations of levodopa or prevent the occurrence of complications with concomitant use of dopamine agonists, these disabling side effects continue to be a major problem in patients with PD.
Over the past two decades, several investigators have explored the possibility of long-term continuous replacement of dopamine into the striatum using dopaminergic cell transplantation. Initial studies by Backlund et al showed the feasibility and efficacy of adrenal medullary dopaminergic cell transplantation into the striatum. Since then, several other types of dopaminergic cells have been transplanted successfully into animal models of PD and in humans to ameliorate parkinsonism. The greatest clinical benefit reported to date with dopaminergic cell transplantation has been using allogeneic human fetal ventral mesencephalic (FVM) tissue transplantation. Transplantation of fetal dopaminergic cells in PD has the advantage of potentially providing a continuous replenishment of dopamine and thus the ability to avoid or ameliorate the complications of chronic intermittent levodopa therapy. Second, FVM cells survive and make appropriate synaptic connections with the host, suggesting that these transplanted cells are capable of regulation of their dopamine output and therefore provide a more physiologic treatment option than other treatments such as ablative surgery or deep brain stimulation (DBS). Third, the next generation of high-quality dopaminergic cells (e.g., porcine fetal mesencephalic cells, human retinal pigmented epithelial cells, and progenitor cells) are in advanced stages of clinical or preclinical testing and likely to become available in the near future as a therapeutic modality in PD.
Cell transplantation is an experimental therapy for Parkinson's disease (PD) and other movement disorders. Several open-label research trials have shown clinically meaningful improvement in parkinsonian signs and symptoms after striatal transplantation of allogeneic fetal ventral mesencephalic (FVM) tissue. However, ethical concerns, variability in surgical techniques, and reports of unusual late complications in a few patients in a clinical trial have limited the use of allogeneic FVM tissue to a few research centers. Research into alternative cell sources such as porcine FVM and allogeneic retinal pigment epithelial cells has shown promising results in preclinical trials, and they are currently being tested in clinical trials. Novel strategies to improve cell survival and to avoid immune rejection of transplants show promising results in preclinical trials. This article focuses on these recent advances and compares the potential clinical utility of these emerging cell therapies for the treatment of advanced PD.
Objectives: On completion of this article, the reader will understand current concepts of cell transplantation as experimental therapy for involuntary movement disorders.
Accreditation: The Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit: The Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.
Disclosure: Statements have been obtained regarding the author's relationships with financial supporters of this activity. There is no apparent conflict of interest related to the context of participation of the author of this article. Dr. Subramanian has served as a paid consultant for Titan Pharmaceuticals, Inc., and has received research grants from Titan Pharmaceuticals, Inc. and Diacrin-Genzyme, LLC.
Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic neurons in the substantia nigra (SN). Dopaminergic neurons in the SN have their cell bodies located in a compact area on the dorsomedial aspect of the nucleus called the SN pars compacta (SNc). These neurons give rise to long axonal projections into the caudate nucleus and the putamen and make short dendritic connections to the neurons in the SN pars reticulata (SNr). The pathophysiology of PD has been attributed to the dramatic drop in dopamine content within the striatum (particularly in the postcommisural putamen) secondary to the degeneration of SNc neurons. This results in disinhibition of the subthalamic nucleus (STN), resulting in increased internal globus pallidum and SNr output. The net result is the inhibition of cortical motor neurons. Pharmacological therapeutic strategies for PD are currently centered around replacement of dopamine in the brain either by exogenous supplementation of dopamine precursors (levodopa), dopamine agonists, cathecol-O-methyltransferase (COMT) inhibitors, or drugs that modulate glutamate- or acetylcholine-mediated neurotransmission.
The discovery of levodopa, a precursor of dopamine and the most potent oral dopaminergic agent to date to ameliorate parkinsonism, revolutionized the treatment of PD in the 1960s, and it continues to be the best available treatment for PD. However, chronic intermittent treatment with levodopa leads to disabling side effects in the majority of patients with Parkinson's disease. It has been shown that continuous systemic administration (intravenous or intraduodenal) of levodopa can prevent the occurrence of these disabling side effects. However, these methods of administration are impractical and unacceptable to patients with PD. Although many attempts have been made to produce continuous-release oral preparations of levodopa or prevent the occurrence of complications with concomitant use of dopamine agonists, these disabling side effects continue to be a major problem in patients with PD.
Over the past two decades, several investigators have explored the possibility of long-term continuous replacement of dopamine into the striatum using dopaminergic cell transplantation. Initial studies by Backlund et al showed the feasibility and efficacy of adrenal medullary dopaminergic cell transplantation into the striatum. Since then, several other types of dopaminergic cells have been transplanted successfully into animal models of PD and in humans to ameliorate parkinsonism. The greatest clinical benefit reported to date with dopaminergic cell transplantation has been using allogeneic human fetal ventral mesencephalic (FVM) tissue transplantation. Transplantation of fetal dopaminergic cells in PD has the advantage of potentially providing a continuous replenishment of dopamine and thus the ability to avoid or ameliorate the complications of chronic intermittent levodopa therapy. Second, FVM cells survive and make appropriate synaptic connections with the host, suggesting that these transplanted cells are capable of regulation of their dopamine output and therefore provide a more physiologic treatment option than other treatments such as ablative surgery or deep brain stimulation (DBS). Third, the next generation of high-quality dopaminergic cells (e.g., porcine fetal mesencephalic cells, human retinal pigmented epithelial cells, and progenitor cells) are in advanced stages of clinical or preclinical testing and likely to become available in the near future as a therapeutic modality in PD.
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