Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line—derived neurotrophic factor

2005 ◽  
Vol 102 (2) ◽  
pp. 216-222 ◽  
Author(s):  
John T. Slevin ◽  
Greg A. Gerhardt ◽  
Charles D. Smith ◽  
Don M. Gash ◽  
Richard Kryscio ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Rating Scale ◽  
Open Label ◽  
Content Type ◽  
Potential Efficacy ◽  
Bilateral Effects ◽  
Fine Print

Object. Glial cell line-derived neurotrophic factor (GDNF) has demonstrated significant antiparkinsonian actions in several animal models and in a recent pilot study in England in which four of five patients received bilateral putaminal delivery. In the present study the authors report on a 6-month unilateral intraputaminal GDNF infusion in 10 patients with advanced Parkinson disease (PD). Methods. Patients with PD in a functionally defined on and off state were evaluated 1 week before and 1 and 4 weeks after intraputaminal catheter implantation in the side contralateral to the most affected side. Each patient was placed on a dose-escalation regimen of GDNF: 3, 10, and 30 µg/day at successive 8-week intervals, followed by a 1-month wash-out period. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores in the on and off states significantly improved 34 and 33%, respectively, at 24 weeks compared with baseline scores (95% confidence interval [CI] 18–47% for off scores and 16–51% for on scores). In addition, UPDRS motor scores in both the on and off states significantly improved by 30% at 24 weeks compared with baseline scores (95% CI 15–48% for off scores and 5–61% for on scores). Improvements occurred bilaterally, as measured by balance and gait and increased speed of hand movements. All significant improvements of motor function continued through the wash-out period. The only observed side effects were transient Lhermitte symptoms in two patients. Conclusions. Analysis of the data in this open-label study demonstrates the safety and potential efficacy of unilateral intraputaminal GDNF infusion. Unilateral administration of the protein resulted in significant, sustained bilateral effects.

Glial cell line—derived neurotrophic factor—supplemented hibernation of fetal ventral mesencephalic neurons for transplantation in Parkinson disease: long-term storage

2003 ◽  
Vol 98 (5) ◽  
pp. 1078-1083 ◽  
Author(s):  
Adam O. Hebb ◽  
Kari Hebb ◽  
Arun C. Ramachandran ◽  
Ivar Mendez
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Storage Time ◽  
Fetal Tissue ◽  
Control Group ◽  
Content Type ◽  
Cell Counts ◽  
Fine Print

Object. Transplantation of fetal dopaminergic tissue is being investigated in animal models and clinical trials for its potential as a treatment for advanced Parkinson disease. At the same time, the availability of fetal tissue is limited, making its storage time prior to transplantation a key practical issue. Although it results in a smaller percentage of surviving cells, a longer storage time enables fetal tissue obtained over several days to be pooled for transplantation in a recipient. Glial cell line—derived neurotrophic factor (GDNF) has been shown to improve survival of human dopaminergic tissue that has been stored prior to transplantation. The objective of this study was to evaluate the effects on fetal dopaminergic tissue of GDNF-supplemented hibernation for extended periods of 6 to 15 days. Methods. The ventral mesencephalon (VM) was harvested in a total of 27 14-day-old rat fetuses, and three VMs were cultured immediately (fresh control group). The remaining 24 VMs were divided sagittally along the midline to yield 48 equal pieces of hemimesencephalon. Twenty-four pieces were stored with GDNF-supplemented hibernation medium for 6, 9, 12, or 15 days, and the 24 “partner” hemimesencephalon pieces were stored in control hibernation medium for the same periods of time. Tissue was cultured for 48 hours and processed for tyrosine hydroxylase (TH) immunoreactivity and double-stained with cresyl violet. Cell counts for all cultures and the percentage of TH-immunoreactive cells were obtained. The percentage of TH-immunoreactive cells for the fresh control group was 6.3 ± 0.5%. The percentage of TH-immunoreactive cells in cultures derived from tissue stored in GDNF-supplemented medium was significantly increased at 6 and 9 days posthibernation compared with the fresh control group and the “partner” groups stored in hibernation medium only. No significant increase in the percentage of TH-immunoreactive cells was observed in the 12- and 15-day groups. Conclusions. In this study the authors have demonstrated that fetal dopaminergic tissue can be safely stored for up to 9 days in GDNF-supplemented hibernation medium. Furthermore, the percentage of TH-immunoreactive cells is significantly increased after 6 and 9 days of storage in this medium, improving the yield of TH-immunoreactive cells prior to transplantation. These observations have practical clinical implications for collecting fetal dopaminergic cells and improving their survival after transplantation.

Early transplantation of an encapsulated glial cell line—derived neurotrophic factor—producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease

2005 ◽  
Vol 102 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Takao Yasuhara ◽  
Tetsuro Shingo ◽  
Kenichiro Muraoka ◽  
Kazuki Kobayashi ◽  
Akira Takeuchi ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Rat Model ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effects ◽  
Content Type ◽  
Glial Proliferation ◽  
Fine Print

Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo. Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.

Promotion of survival and regeneration of nigral dopamine neurons in a rat model of Parkinson's disease after implantation of embryonal carcinoma—derived neurons genetically engineered to produce glial cell line—derived neurotrophic factor

2000 ◽  
Vol 92 (4) ◽  
pp. 659-670 ◽  
Author(s):  
Naoyuki Nakao ◽  
Hideyuki Yokote ◽  
Kunio Nakai ◽  
Toru Itakura
Keyword(s):  
Cell Line ◽  
Glial Cell ◽  
Rat Model ◽  
Neurotrophic Factor ◽  
Embryonal Carcinoma ◽  
Genetically Engineered ◽  
P19 Cells ◽  
Content Type ◽  
Postmitotic Neurons ◽  
Fine Print

Object. The P19 embryonal carcinoma—derived cell line consists of undifferentiated multipotential cells, which irreversibly differentiate into mature neurons after exposure to retinoic acid (RA). In the present study, the authors genetically engineered P19 cells to produce glial cell line—derived neurotrophic factor (GDNF), and grafted the cells in a rat model that had been rendered parkinsonian.Methods. Undifferentiated P19 cells were grown in vitro and transduced with GDNF complementary DNA. The level of GDNF released from the transduced cells was measured using an enzyme-linked immunosorbent assay, and its neurotrophic activities were assessed by testing the effects on rat embryonic dopamine (DA) neurons in culture. After having been exposed to RA for 48 hours and allowed to differentiate into postmitotic neurons, the GDNF gene—transduced cells were implanted into the midbrain of immunosuppressed rats. A unilateral nigrostriatal lesion was then induced by intrastriatal infusions of 6-hydroxydopamine. Immunohistochemical analyses performed 4 weeks postgrafting revealed that the GDNF-producing cells expressed several neuronal markers without evidence of overgrowth. The grafts expressed GDNF protein and prevented the death of nigral DA neurons. Furthermore, the GDNF-producing cells implanted 4 weeks after nigrostriatal lesions restored the expression of tyrosine hydroxylase in injured DA neurons and induced their dendritic sprouting.Conclusions. The results indicate that the P19 cell line transduced with the GDNF gene can stably secrete functional levels of GDNF, even after being converted to postmitotic neurons. Because it is has been established that GDNF exerts trophic effects on DA neurons, the means currently used to deliver GDNF into the brain could be a viable strategy to prevent the death of nigral DA neurons in cases of Parkinson's disease.

Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up

2003 ◽  
Vol 99 (1) ◽  
pp. 71-77 ◽  
Author(s):  
Rajesh Pahwa ◽  
Steven B. Wilkinson ◽  
John Overman ◽  
Kelly E. Lyons
Keyword(s):  
Parkinson Disease ◽  
Rating Scale ◽  
Pulse Generator ◽  
Visual Disturbance ◽  
Open Label ◽  
Content Type ◽  
Long Term Follow Up ◽  
Fine Print

Object. Bilateral subthalamic nucleus (STN) stimulation is increasingly used in patients with advanced Parkinson disease (PD). This study was performed to evaluate the long-term efficacy and safety of bilateral STN stimulation in cases of PD. Methods. The authors performed a prospective, open-label study in patients with PD who underwent bilateral STN stimulation. The authors compared motor scores and activities of daily living (ADL) scores based on the Unified PD Rating Scale (UPDRS) obtained before surgery while patients were in the medication-off state with scores obtained at follow-up evaluations of these patients while in the medication-off/stimulator-on state. Data contained in patient diaries were also compared. Thirty-three patients with PD were evaluated 12 months postoperatively and 19 were evaluated at a mean follow-up time of 28 months. A comparison between UPDRS scores obtained in patients in the medication-off/stimulator-on state and those obtained when patients were in the baseline medication-off state showed a 27% improvement in ADL scores and a 28% improvement in motor scores after surgery. There was a 57% reduction in the use of levodopa-equivalent medication doses. The percentage of the waking day that patients were in the medication-on state increased from 38 to 72%. Surgical complications included seizures (three patients), confusion (five patients), hemiballismus (one patient), and visual disturbance (one patient). Stimulation-related adverse effects were mild. Device-related events included nine lead replacements, seven lead revisions, six extension replacements, and 12 implantable pulse generator (IPG) replacements; one IPG was cleaned and one IPG was placed in a pocket because of the presence of a shunt. Conclusions. Bilateral STN simulation is associated with a significant improvement in the motor features of PD. Device-related events were common in the first 20 patients who underwent surgery, often requiring repeated surgeries.

Protective effects of glial cell line—derived neurotrophic factor on hippocampal neurons after traumatic brain injury in rats

2001 ◽  
Vol 95 (4) ◽  
pp. 674-679 ◽  
Author(s):  
Bum-Tae Kim ◽  
Vemuganti L. Raghavendra Rao ◽  
Kurt A. Sailor ◽  
Kellie K. Bowen ◽  
Robert J. Dempsey
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Neuronal Loss ◽  
Content Type ◽  
Frontal Horn ◽  
Brain Injured ◽  
Fine Print

Object. The purpose of this study was to evaluate whether glial cell line—derived neurotrophic factor (GDNF) can protect against hippocampal neuronal death after traumatic brain injury (TBI). Methods. Male Sprague—Dawley rats were subjected to moderate TBI with a controlled cortical impact device while in a state of halothane-induced anesthesia. Then, GDNF or artificial cerebrospinal fluid ([aCSF]; vehicle) was infused into the frontal horn of the left lateral ventricle. In eight brain-injured and eight sham-operated rats, GDNF was infused continuously for 7 days (200 ng/day intracerebroventricularly at a rate of 8.35 ng/0.5 µl/hour). An equal volume of vehicle was infused at the same rate into the remaining eight brain-injured and eight sham-operated rats. Seven days post-injury, all rats were killed. Their brains were sectioned and stained with cresyl violet, and the hippocampal neuronal loss was evaluated in the CA2 and CA3 regions with the aid of microscopy. A parallel set of sections from each brain was subjected to immunoreaction with antibodies against glial fibrillary acidic protein (GFAP; astroglia marker). In the aCSF-treated group, TBI resulted in a significant neuronal loss in the CA2 (60%, p < 0.05) and CA3 regions (68%, p < 0.05) compared with the sham-operated control animals. Compared with control rats infused with aCSF, GDNF infusion significantly decreased the TBI-induced neuronal loss in both the CA2 (58%, p < 0.05) and CA3 regions (51%, p < 0.05). There was no difference in the number of GFAP-positive astroglial cells in the GDNF-infused rats in the TBI and sham-operated groups compared with the respective vehicle-treated groups. Conclusions. The authors found that GDNF treatment following TBI is neuroprotective.

Unilateral intraputaminal glial cell line–derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal

2006 ◽  
Vol 20 (5) ◽  
pp. 1-7 ◽  
Author(s):  
John T. Slevin ◽  
Don M. Gash ◽  
Charles D. Smith ◽  
Greg A. Gerhardt ◽  
Richard Kryscio ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Delivery System ◽  
Neurotrophic Factor ◽  
Infusion Rate ◽  
Rating Scale ◽  
Drug Withdrawal ◽  
Continuous Treatment ◽  
Convection Enhanced Delivery

Object Glial cell line–derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months was previously shown to improve motor functions and quality of life measures significantly in 10 patients with Parkinson disease (PD) in a Phase I trial. In this study the authors report the safety and efficacy of continuous treatment for 1 year or more. After the trial was halted by the sponsor, the patients were monitored for an additional year to evaluate the effects of drug withdrawal. Methods During the extended study, patients received unilateral intraputaminal infusion of 30 μg/day GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 μl/hour. The Unified PD Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38%, respectively, in the “off” and “on” states. Motor UPDRS scores were also improved: 45 and 39% in the off and on conditions, respectively. Benefits from treatment were lost by 9 to 12 months after GDNF infusion was halted. At that time, the patients had returned to their baseline UPDRS scores and required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of the risk of infection. In seven patients antibodies to GDNF developed, with no evidence of clinical sequelae. There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing. Conclusions Unilateral administration of GDNF results in significant, sustained bilateral benefits. These improvements are lost within 9 months after drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.

Unilateral intraputamenal glial cell line–derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal

2007 ◽  
Vol 106 (4) ◽  
pp. 614-620 ◽  
Author(s):  
John T. Slevin ◽  
Don M. Gash ◽  
Charles D. Smith ◽  
Greg A. Gerhardt ◽  
Richard Kryscio ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Delivery System ◽  
Neurotrophic Factor ◽  
Infusion Rate ◽  
Rating Scale ◽  
Drug Withdrawal ◽  
Continuous Treatment ◽  
Convection Enhanced Delivery

Object Glial cell line–derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months has been previously shown to improve significantly motor functions and quality of life measures in 10 patients with Parkinson disease (PD) in a Phase I trial. In the present study the authors report the safety and efficacy of continuous treatment for a minimum of 1 year. After the trial was halted by the drug sponsor, the patients were monitored for an additional 1 year during which the effects of drug withdrawal were evaluated. Methods During the extended study period, patients received a 30-μg/day unilateral intraputamenal infusion of GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 μl/hour. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38% in the off- and on-medication states; the motor UPDRS scores were also improved 45 and 39%, respectively. Benefits from treatment were lost by 9 to 12 months after the cessation of GDNF infusion. The UPDRS scores returned to their baseline and the patients required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of risk of infection. Seven patients developed antibodies to GDNF but without evident clinical sequelae. There was no evidence for GDNF-induced cerebellar toxicity, as evaluated by magnetic resonance imaging and clinical testing. Conclusions The unilateral administration of GDNF results in significant, sustained bilateral benefits in patients with PD. These improvements are lost within 9 months of drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.

Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line—derived neurotrophic factor

1998 ◽  
Vol 88 (6) ◽  
pp. 1088-1095 ◽  
Author(s):  
Vivek Mehta ◽  
Murray Hong ◽  
Julian Spears ◽  
Ivar Mendez
Keyword(s):  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Fetal Tissue ◽  
Cell Number ◽  
Genetically Engineered ◽  
Nigrostriatal Pathway ◽  
Content Type ◽  
6 Hydroxydopamine ◽  
Fine Print

Object. The goal of this study was to investigate the ability of fetal dopaminergic neurons to improve complex sensorimotor behavior. Methods. The authors obtained ventral mesencephalic tissue from 14-day-old rat fetuses. The cells were exposed to glial cell line—derived neurotrophic factor (GDNF) prior to transplantation into rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway. Animals that received 400,000 cells exposed to GDNF demonstrated significant improvement in contralateral forelimb function and showed improvement in rotational behavior faster than animals that received cells not exposed to GDNF. Increasing the number of implanted cells to 800,000 exposed to GDNF did not result in any additional improvement in functional recovery. Conclusions. As neural grafting procedures in the nervous system evolve and genetically engineered cells or stem cells replace fetal tissue, crucial questions about cell number and trophic regulation will need to be addressed. This study demonstrates that grafting of 400,000 cells exposed to GDNF before transplantation has a beneficial effect in the restoration of complex sensorimotor behavior.

scholarly journals The Parkinson’s Disease Comprehensive Response (PDCORE): a composite approach integrating three standard outcome measures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Matthias Luz ◽  
Alan Whone ◽  
Niccolò Bassani ◽  
Richard K Wyse ◽  
Glenn T Stebbins ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Rating Scale ◽  
Initial Development ◽  
Disease Rating ◽  
Recent Phase ◽  
Data Source

Abstract There is an increasing need for improved endpoints to assess clinical trial effects in Parkinson’s disease. We propose the Parkinson’s Disease Comprehensive Response as a novel weighted composite endpoint integrating changes measured in three established Parkinson’s outcomes, including: OFF state Movement Disorder Society Unified Parkinson’s Disease Rating Scale Motor Examination scores; Motor Experiences of Daily Living scores; and total good-quality ON time per day. The data source for the initial development of the composite described herein was a recent Phase II trial of glial cell line-derived neurotrophic factor. A wide range of clinically derived relative weights was assessed to normalize for differentially scoring base rates with each endpoint component. The Parkinson’s disease comprehensive response, in contrast to examining practically defined OFF state Unified Parkinson’s Disease Rating Scale Motor Examination scores alone, showed stability over 40 weeks in placebo patients, and all 432 analyses in this permutation exercise yielded significant differences in favour of glial cell line-derived neurotrophic factor. The findings were consistent with results obtained employing three different global statistical test methodologies and with patterns of intra-patient change. Based on our detailed analyses, we conclude it worth prospectively evaluating the clinical utility, validity and regulatory feasibility of using clinically supported final Parkinson’s disease comprehensive response formulas (for both the Unified Parkinson’s Disease Rating Scale-based and Movement Disorders Society-Unified Parkinson’s Disease Rating Scale-based versions) in future disease-modifying Parkinson’s trials. Whilst the data source employed in the initial development of this weighted composite score is from a recent Phase II trial of glial cell line-derived neurotrophic factor, we wish to stress that the results are not described to provide post hoc evidence of the efficacy of glial cell line-derived neurotrophic factor but rather are presented to further the debate of how current regulatory approved rating scales may be combined to address some of the recognized limitations of using individual scales in isolation.

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