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Parkinson's Disease
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Re: Alzheimer’s
Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate upregulates DJ-1 and protects neurons in cell culture and in animal models of Parkinson's disease. Journal of Biological Chemistry. http://www.jbc.org/content/early/2011/03/03/jbc.M110.211029.full.pdf
Parkinson's disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati and colleagues found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson's disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant and gene regulatory activity of the DJ-1 protein. Since low levels of DJ-1 cause Parkinson's, we reasoned that over-expression might stop the disease. We found that over-expression of DJ-1 improved tolerance to oxidative stress by selectively up-regulating the rate limiting step in glutathione synthesis. When we imposed a different metabolic insult, A53T mutant alpha-synuclein, we found that DJ-1 turned on production of the chaperone protein Hsp-70 without affecting glutathione synthesis. After screening a number of small molecules, we have found that the histone deacetylase inhibitor phenylbutyrate increases DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant alpha-synuclein toxicity. In mice, phenylbutyrate treatment leads to a 260% increase in brain DJ-1 levels and protects dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduces alpha-synuclein aggregation in brain and prevents age-related deterioration in motor and cognitive function. We conclude that drugs that upregulate DJ-1 gene expression may slow the progression of Parkinson's disease by moderating oxidative stress and protein aggregation.
Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate upregulates DJ-1 and protects neurons in cell culture and in animal models of Parkinson's disease. Journal of Biological Chemistry. http://www.jbc.org/content/early/2011/03/03/jbc.M110.211029.full.pdf
Parkinson's disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati and colleagues found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson's disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant and gene regulatory activity of the DJ-1 protein. Since low levels of DJ-1 cause Parkinson's, we reasoned that over-expression might stop the disease. We found that over-expression of DJ-1 improved tolerance to oxidative stress by selectively up-regulating the rate limiting step in glutathione synthesis. When we imposed a different metabolic insult, A53T mutant alpha-synuclein, we found that DJ-1 turned on production of the chaperone protein Hsp-70 without affecting glutathione synthesis. After screening a number of small molecules, we have found that the histone deacetylase inhibitor phenylbutyrate increases DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant alpha-synuclein toxicity. In mice, phenylbutyrate treatment leads to a 260% increase in brain DJ-1 levels and protects dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduces alpha-synuclein aggregation in brain and prevents age-related deterioration in motor and cognitive function. We conclude that drugs that upregulate DJ-1 gene expression may slow the progression of Parkinson's disease by moderating oxidative stress and protein aggregation.
Pico-Tesla, Magnetic Therapies, LLC is a medical research and device development company that has designed, patented and manufactured a system that provides an internet-enabled platform technology to therapeutically address several major areas of disease. Our lead indication and current area of focus is Parkinson’s Disease (PD). http://www.pico-tesla.com/index.html
Gene Therapy For Advanced Parkinson's Disease
Neurodegeneration of dopaminergic neurons underlies the motor manifestations of Parkinson’s disease. When mild, Parkinson’s disease is generally well controlled by drugs; however, as the disease progresses, pharmacotherapy often fails to provide adequate symptom relief and sometimes causes disabling complications, such as motor fluctuations. Additional treatment approaches, such as deep brain stimulation (DBS) and pharmacological interventions at sites beyond the nigrostriatal dopaminergic pathway have been used to manage problems of advanced Parkinson’s disease. In vivo gene therapy is a new approach. Despite promising results in animal models of parkinsonism and in several open-label clinical investigations, the efficacy of gene therapy has yet to be confirmed in a randomized double-blind clinical trial. In Parkinson’s disease, loss of nigrostriatal dopaminergic neurons alters striato-pallidal circuitry such that decreased GABA input to the subthalamic nucleus renders this structure disinhibited. Treatments that diminish or modulate the activity of the subthalamic nucleus, such as subthalamotomy and DBS, can help with some parkinsonian symptoms. Like dopaminergic treatment, however, DBS can fail to improve some parkinsonian features such as freezing of gait, imbalance, dysphagia, cognitive and psychiatric problems, and speech difficulties. Furthermore, this technique necessitates implantation of devices and much effort to adjust electrical stimulation variables.
Gene therapy consisting of insertion of the glutamic acid decarboxylase gene (GAD) into the subthalamic nucleus may offer an alternative therapeutic strategy. GAD is the rate-limiting enzyme for GABA production, and the activity of both GABA efferents to the subthalamic nucleus and its targets within the basal ganglia circuitry are affected in Parkinson’s disease. During DBS surgery in patients with this disease, an infusion of the GABAergic agonist muscimol into the subthalamic nucleus suppressed its neuronal firing rates and temporarily improved parkinsonian symptoms, suggesting that improvement of GABA transmission within the subthalamic nucleus could be beneficial in Parkinson’s disease. Similar results in animal models of parkinsonism were achieved with gene transfer of GAD. This strategy uses an adeno-associated viral vector (AAV2) to deliver GAD to the subthalamic nucleus to both restore local GABA transmission within the nucleus and to normalize output from the nucleus (by adding an inhibitory GABA outflow, thereby reducing excessive excitatory glutamate output to key targets such as the globus pallidus interna and the substantia nigra reticulata). An open-label clinical trial of AAV2-GAD injected unilaterally into the subthalamic nucleus showed this procedure to be safe and associated with improvements of parkinsonism. Although studies of other gene, cell, and biological therapies in patients with Parkinson’s disease have also shown promise in small, open-label studies, subsequent randomized double-blind clinical trials have not substantiated their initial findings. Consequently, progress in the assessment of CNS gene therapy needs careful attention to all aspects of study methods, including sham procedures, effective blinding, and successful delivery of the experimental therapy to the intended targets. This trial was done to assess the effect of bilateral delivery of AAV2-GAD into the subthalamic nucleus compared with bilateral sham surgery in patients with advanced Parkinson’s disease.
LeWitt PA, Rezai AR, Leehey MA, et al. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. The Lancet Neurology. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial : The Lancet Neurology
Background - Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease.
Methods - Patients aged 30—75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores.
Findings - Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8•1 points (SD 1•7, 23•1%; p<0•0001) and by 4•7 points in the sham group (1•5, 12•7%; p=0•003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0•04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD groupvs two in the sham group) and nausea (six vs two).
Interpretation - The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders.
Neurodegeneration of dopaminergic neurons underlies the motor manifestations of Parkinson’s disease. When mild, Parkinson’s disease is generally well controlled by drugs; however, as the disease progresses, pharmacotherapy often fails to provide adequate symptom relief and sometimes causes disabling complications, such as motor fluctuations. Additional treatment approaches, such as deep brain stimulation (DBS) and pharmacological interventions at sites beyond the nigrostriatal dopaminergic pathway have been used to manage problems of advanced Parkinson’s disease. In vivo gene therapy is a new approach. Despite promising results in animal models of parkinsonism and in several open-label clinical investigations, the efficacy of gene therapy has yet to be confirmed in a randomized double-blind clinical trial. In Parkinson’s disease, loss of nigrostriatal dopaminergic neurons alters striato-pallidal circuitry such that decreased GABA input to the subthalamic nucleus renders this structure disinhibited. Treatments that diminish or modulate the activity of the subthalamic nucleus, such as subthalamotomy and DBS, can help with some parkinsonian symptoms. Like dopaminergic treatment, however, DBS can fail to improve some parkinsonian features such as freezing of gait, imbalance, dysphagia, cognitive and psychiatric problems, and speech difficulties. Furthermore, this technique necessitates implantation of devices and much effort to adjust electrical stimulation variables.
Gene therapy consisting of insertion of the glutamic acid decarboxylase gene (GAD) into the subthalamic nucleus may offer an alternative therapeutic strategy. GAD is the rate-limiting enzyme for GABA production, and the activity of both GABA efferents to the subthalamic nucleus and its targets within the basal ganglia circuitry are affected in Parkinson’s disease. During DBS surgery in patients with this disease, an infusion of the GABAergic agonist muscimol into the subthalamic nucleus suppressed its neuronal firing rates and temporarily improved parkinsonian symptoms, suggesting that improvement of GABA transmission within the subthalamic nucleus could be beneficial in Parkinson’s disease. Similar results in animal models of parkinsonism were achieved with gene transfer of GAD. This strategy uses an adeno-associated viral vector (AAV2) to deliver GAD to the subthalamic nucleus to both restore local GABA transmission within the nucleus and to normalize output from the nucleus (by adding an inhibitory GABA outflow, thereby reducing excessive excitatory glutamate output to key targets such as the globus pallidus interna and the substantia nigra reticulata). An open-label clinical trial of AAV2-GAD injected unilaterally into the subthalamic nucleus showed this procedure to be safe and associated with improvements of parkinsonism. Although studies of other gene, cell, and biological therapies in patients with Parkinson’s disease have also shown promise in small, open-label studies, subsequent randomized double-blind clinical trials have not substantiated their initial findings. Consequently, progress in the assessment of CNS gene therapy needs careful attention to all aspects of study methods, including sham procedures, effective blinding, and successful delivery of the experimental therapy to the intended targets. This trial was done to assess the effect of bilateral delivery of AAV2-GAD into the subthalamic nucleus compared with bilateral sham surgery in patients with advanced Parkinson’s disease.
LeWitt PA, Rezai AR, Leehey MA, et al. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. The Lancet Neurology. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial : The Lancet Neurology
Background - Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease.
Methods - Patients aged 30—75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores.
Findings - Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8•1 points (SD 1•7, 23•1%; p<0•0001) and by 4•7 points in the sham group (1•5, 12•7%; p=0•003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0•04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD groupvs two in the sham group) and nausea (six vs two).
Interpretation - The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders.
paulmartin
Banned
Parkinson's disease, which usually affects people over age 50, is a progressive disorder that gradually deteriorates nerve cells in the brain. The gene therapy approach in the current study acts on an alternative neurotransmitter system of the brain involving a signaling chemical called GABA. Another treatment involves permanently implanting a medical nerve-control device in the brain called deep brain stimulation.
Re: Alzheimer’s
Prosavin
Just heard on the radio that this is showing promising results in the UK for treatment of Parkinson's.
http://www.oxfordbiomedica.co.uk/page.asp?pageid=29 (Oxford BioMedica)
Prosavin
Just heard on the radio that this is showing promising results in the UK for treatment of Parkinson's.
http://www.oxfordbiomedica.co.uk/page.asp?pageid=29 (Oxford BioMedica)
Google's Brin Makes Strides on Parkinson's Cure
Google's Brin Makes Strides on Parkinson's Cure - Businessweek
Google's Brin Makes Strides on Parkinson's Cure - Businessweek
http://www.tocris.com/dispprod.php?ItemId=5218 (4-Phenylbutyrate, sodium Supplier | CAS 1716-12-7 | Tocris Bioscience | 4-PB | Sodium Phenylbutyrate)
Buphenyl (Sodium Phenylbutyrate Tablets) Drug Information: Indications, Dosage and How Supplied - Prescribing Information at RxList
Buphenyl (Sodium Phenylbutyrate Tablets) Drug Information: Indications, Dosage and How Supplied - Prescribing Information at RxList
Kareus SA, Figueroa KP, Cannon-Albright LA, Pulst SM. Shared Predispositions of Parkinsonism and Cancer: A Population-Based Pedigree-Linked Study. Arch Neurol. Published online September 03, 2012. JAMA Network | Archives of Neurology | Shared Predispositions of Parkinsonism and CancerA Population-Based Pedigree-Linked StudyShared Predispositions of Parkinsonism and Cancer
Objective To use a statewide population-based genealogic database to evaluate the relationship between Parkinson disease (PD) and cancer subtypes.
Design Using a computerized genealogy for the Utah pioneers and their descendants linked to a statewide cancer registry and statewide death certificates, we estimated relative risks for cancer in individuals with PD listed on their death certificate, and in their first-degree, second-degree, and third-degree relatives.
Setting Utah Cancer Registry.
Participants Approximately 2.3 million individuals in the Utah genealogic resource, including death certificates of 2998 individuals with PD listed as a cause of death from 1904 to 2008 and information on 100 817 individuals with a cancer diagnosis in the Utah Cancer Registry.
Results Melanoma and prostate cancer were the only cancers observed in significant excess among PD cases; colorectal, lung, pancreas, and stomach cancers were observed in deficit. A significantly increased risk for prostate cancer was observed in the PD population as well as among their relatives. A reciprocal significantly increased risk for PD was also found in the 22 147 prostate cancer cases and their relatives. A significantly elevated risk for melanoma was found in the Utah PD population as well as in their relatives. A reciprocal significantly increased relative risk for PD was found in 7841 Utah melanoma cases and their relatives.
Conclusions Our study identified a novel association between PD and prostate cancer, which extended to first-degree, second-degree, and third-degree relatives. We also confirmed the reported risk association for melanoma in patients with PD; we extended the finding to include a significantly increased risk in relatives. These results strongly support a genetic link. This conclusion is further strengthened by observation of the reciprocal relationship, an increased risk for PD in relatives of individuals with melanoma or prostate cancer.
Objective To use a statewide population-based genealogic database to evaluate the relationship between Parkinson disease (PD) and cancer subtypes.
Design Using a computerized genealogy for the Utah pioneers and their descendants linked to a statewide cancer registry and statewide death certificates, we estimated relative risks for cancer in individuals with PD listed on their death certificate, and in their first-degree, second-degree, and third-degree relatives.
Setting Utah Cancer Registry.
Participants Approximately 2.3 million individuals in the Utah genealogic resource, including death certificates of 2998 individuals with PD listed as a cause of death from 1904 to 2008 and information on 100 817 individuals with a cancer diagnosis in the Utah Cancer Registry.
Results Melanoma and prostate cancer were the only cancers observed in significant excess among PD cases; colorectal, lung, pancreas, and stomach cancers were observed in deficit. A significantly increased risk for prostate cancer was observed in the PD population as well as among their relatives. A reciprocal significantly increased risk for PD was also found in the 22 147 prostate cancer cases and their relatives. A significantly elevated risk for melanoma was found in the Utah PD population as well as in their relatives. A reciprocal significantly increased relative risk for PD was found in 7841 Utah melanoma cases and their relatives.
Conclusions Our study identified a novel association between PD and prostate cancer, which extended to first-degree, second-degree, and third-degree relatives. We also confirmed the reported risk association for melanoma in patients with PD; we extended the finding to include a significantly increased risk in relatives. These results strongly support a genetic link. This conclusion is further strengthened by observation of the reciprocal relationship, an increased risk for PD in relatives of individuals with melanoma or prostate cancer.
Luk KC, Kehm V, Carroll J, et al. Pathological ?-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice. Science 2012;338(6109):949-53. Pathological ?-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice
Parkinson’s disease is characterized by abundant ?-synuclein (?-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic ?-Syn fibrils led to the cell-to-cell transmission of pathologic ?-Syn and Parkinson’s-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic ?-Syn and the cardinal features of Parkinson’s disease.
Parkinson’s disease is characterized by abundant ?-synuclein (?-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic ?-Syn fibrils led to the cell-to-cell transmission of pathologic ?-Syn and Parkinson’s-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic ?-Syn and the cardinal features of Parkinson’s disease.
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