Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant adeno-associated viral (rAAV) vectors are safer and more effective than other in vivo gene delivery methods. Stereotaxic injection of the vectors provides continuous and selective expression of therapeutic proteins throughout the target area in primate brains without toxicity. Three phase I clinical trials for gene therapy for Parkinson's disease (PD) using rAAV vectors are currently underway. One trial involves gene transfer of aromatic L-amino acid decarboxylase (AADC), an enzyme that converts L-dopa to dopamine, to restore therapeutic windows of orally administered L-dopa in advanced idiopathic PD. After AADC transduction, the daily required dose of L-dopa can be reduced and the duration of the ON period is prolonged. Another trial involves transduction of the subthalamic nucleus (STN) with rAAV vectors expressing glutamic acid decarboxylases, a rate-limiting enzyme for synthesizing inhibitory the neurotransmitter gamma-aminobutyric acid (GABA). This strategy, which is similar to deep brain stimulation, aims at modulating hyperactive STN neurons, thereby alter the resulting activity of down-stream targets, which influence movement. However, the mechanism of stimulation remains unknown, and there are some theoretical concerns of chemical alteration. The other trial involves delivery of rAAV vectors expressing neurturin, a natural analog of a glial cell line-derived neurotrophic factor, into the putamen to slow down the ongoing degeneration of nigral dopaminergic neurons. Positron emission tomography with various tracers has been used to monitor the effects of therapeutic gene expression in vivo. Although no serious adverse effects of gene transfer have been reported so far in these trials, vector systems that regulate transgene expression are necessary to increase safety, and the development of such systems is in progress. Gene therapy using rAAV vectors may be a promising option for treatment of PD in the near future.
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PMID:[Gene therapy for Parkinson's disease]. 1744 29

Treatments with potential neuroprotective capability for Parkinson's disease (PD) have been investigated in randomized, controlled, clinical trials and other studies since the mid-1980s. Although promising leads have arisen, no therapy has been proven to halt or slow disease progression. Several large-scale studies have highlighted progress in methodology, as well as the frustrations of translating laboratory science to practical applications. This review summarizes findings from clinical trials with several classes of compounds, including monoamine oxidase-B inhibitors (selegiline, lazabemide, rasagiline), dopaminergic drugs (ropinirole, pramipexole, levodopa), antioxidant strategies (alpha-tocopherol), mitochondrial energy enhancers (coenzyme Q(10), creatine), antiapoptotic agents (TCH346, minocycline, CEP-1347), and antiglutamatergic compounds (riluzole). Beyond small-molecule pharmacology, gene therapy approaches, such as delivering neurotrophic substances (e.g., neurturin) by viral vector, are the next generation of treatment options.
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PMID:Protection against Parkinson's disease progression: clinical experience. 1839 64

After nearly 20 years of preclinical experimentation with various gene delivery approaches in animal models of Parkinson's disease (PD), clinical trials are finally underway. The risk/benefit ratio for these procedures is now generally considered acceptable under approved protocols. The current vehicle for gene delivery to the human brain is recombinant adeno-associated viral vector, which is nonpathogenic and non-self-amplifying. Candidate genes tested in PD patients encode 1) glutamic acid decarboxylase, which is injected into the subthalamic nucleus to catalyze biosynthesis of the inhibitory neurotransmitter gamma-aminobutyric acid and so essentially mimic deep brain stimulation of this nucleus; 2) aromatic l-amino acid decarboxylase, which converts l-dopa to dopamine; and 3) neurturin, a member of the glial cell line-derived neurotrophic factor family. Unraveling the genetic underpinnings of PD could allow gene therapy to go beyond modulating neurotransmission or providing trophic effects to dopaminergic neurons by delivering a specific missing or defective gene. For example, the parkin gene (PARK2) is linked to recessively inherited PD due to loss of function mutations; it prevents alpha-synuclein-induced degeneration of nigral dopaminergic neurons in rats and nonhuman primates. On the other hand, for dominantly inherited Huntington's disease (HD), in which an expanded polyglutamine tract imparts to the protein huntingtin a toxic gain of function, repressing expression of the mutant allele in the striatum using RNA interference technology mitigates pathology and delays the phenotype in a mouse model. Here we review the current state of preclinical and clinical gene therapy studies conducted in PD and HD.
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PMID:Advances in gene therapy for movement disorders. 1839 68

Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.
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PMID:Treatment of Parkinson's disease with trophic factors. 1839 69

The aim of the present study was to investigate the putative cooperative effects of transforming growth factor beta (TGF-beta) and glial cell line-derived neurotrophic factor (GDNF) family ligands in the differentiation of midbrain progenitors toward a dopaminergic phenotype. Therefore, a mouse midbrain embryonic day (E) 12 neurospheres culture was used as an experimental model. We show that neurturin and persephin (PSPN), but not GDNF, are capable of transient induction of dopaminergic neurons in vitro. This process, however, requires the presence of endogenous TGF-beta. In contrast, after 8 days in vitro GDNF rescued the TGF-beta neutralization-dependent loss of the TH-positive cells. In vivo, at E14.5, no apparent phenotype concerning dopaminergic neurons was observed in Tgf-beta2(-/-)/gdnf(-/-) double mutant mice. In vitro, combined TGF-beta/PSPN treatment achieved a yield of approximately 20% TH-positive cells that were less vulnerable against 1-methyl-4-phenyl pyridinium ion toxicity. The underlying TGF-beta/PSPN differentiation signaling is receptor-mediated, involving p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. These results indicate that phenotype induction and survival of fully differentiated neurons are accomplished through distinct pathways and individual factor requirement. TGF-beta is required for the induction of dopaminergic neurons, whereas GDNF is required for regulating and/or maintaining a differentiated neuronal phenotype. Moreover, this study suggests that the combination of TGF-beta with PSPN is a potent inductive cocktail for the generation of dopaminergic neurons that should be considered in tissue engineering and cell replacement therapies for Parkinson's disease.
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PMID:Transforming growth factor beta cooperates with persephin for dopaminergic phenotype induction. 1842 Aug 32

Rasagiline, a selective COMT inhibitor, and rotigotine, a transdermal dopamine (D2) agonist, are two new agents that have been approved in the U.S. and Europe for the treatment of Parkinson's disease. Rasagiline is approved in the U.S. for both monotherapy and as an adjunct to levodopa. Its role in preventing disease progression has yet to be proven, but a large-scale study (ADAGIO) is under way. Rotigotine is approved for early-stage disease in Europe and the U.S. but is only approved in Europe for late-stage disease. It has recently been recalled due to the formation of insoluble crystals that interfere with absorption and may reduce its efficacy. Measures are being taken by the manufacturer to solve this problem. Istradefylline, and adenosine receptor antagonist, showed early promise but efficacy has not been demonstrated consistently, possibly due to higher than expected placebo effect. This has resulted in a nonapprovable letter from the FDA. With regard to perampanel, additional studies are needed to demonstrate safety and efficacy. Sanifamide and pardoprunox are agents that target multiple receptors that may modulate dyskinesia and other nonmotor symptoms in addition to motor symptoms, but phase III data are not yet available. Lusuride is an older dopamine agonist that has been reformulated as a transdermal patch and as a subcutaneous injection and may offer advantages in refractory patients with motor fluctuations. Sphermaine is a novel cell therapy designed to provide a localized source of levodopa directly to the brain. Gene therapies including AAV-GAD, AAV-AADC and AAV2-neurturin are in early stages of development in patients with advanced-stage disease but early safety data are promising.
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PMID:New frontiers in the pharmacological management of Parkinson's disease. 1880 3

Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.
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PMID:Trophic factors therapy in Parkinson's disease. 1966 Jun 58

Glial cell line-derived neurotrophic factor (GDNF) family of ligands (GDFLs) as well as other trophic factors have, in animal models of Parkinson's disease (PD), demonstrated the potential for excellent ameliorative properties. Clinical trials that have mechanically injected GDNF intracerebrally, while demonstrating relative safety, have been clinically disappointing to date. Likewise, recombinant adeno-associated virus (rAAV) delivered neurturin (cere-120) has also been demonstrated to be safe in humans, however clinical results have been negative. The failure of the major clinical trials has cast some doubt in the field about trophic factor delivery for the treatment of PD. In this review, we make the case that GDFLs are likely to function only when there are remaining dopamine neurons in the nigrostriatal pathway as opposed to other candidate modes of action. Thus, it is our view that utilizing earlier stage PD patients who have significant nigrostriatal dopamine innervation remaining would be more ideal to demonstrate the efficacy of GDFLs. This is particularly true when considering a novel delivery method such as gene transfer. However, if earlier stage patients are to be enrolled in GDFL gene transfer trials, then a much better safety profile must be demonstrated by preclinical experiments. One important safety advance might be the use of an external regulation system to control the expression level of the transgene. However, gene regulation systems pose unique safety issues and we will discuss these in detail. It is our view that GDFLs still remain as a promising therapeutic approach for PD.
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PMID:Gene therapy for neurological disorders: challenges and future prospects for the use of growth factors for the treatment of Parkinson's disease. 1986 Jun 52

The core loss of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD) coupled to the therapeutic benefits of dopaminergic therapies in patients, simplifies the treatment strategy for this disease. In the context of neurotrophic factors, this distils down to the simple question as to whether a factor exists for these cells that can promote their survival in the face of the degenerative disease process. If such a factor exists, and GDNF seems a strong candidate, then one could anticipate that this treatment would be as effective as L-dopa therapy. However it would not be better than this, nor curative, given the extensive pathology in PD. To date a number of clinical trials have been undertaken in which GDNF has been directly delivered to the PD brain. In addition there have been studies in which neurturin (part of the GDNF family) has also been delivered to the CNS using a viral vector delivery system. These trials have produced mixed results. Importantly though, some patients have shown a sustained clinical response to this treatment which correlates with evidence of increased dopaminergic activity in the brain at the site of delivery using F-dopa PET as well as in a single post-mortem study. The challenge therefore is not whether this approach works, because it self-evidently does in some patients, but rather how we can do this more consistently.
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PMID:Parkinson's disease and growth factors - are they the answer? 2008 86

Parkinson's disease is the second most common age-related neurodegenerative disorder, typified by the progressive loss of substantia nigra pars compacta dopamine neurons and the consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms, with the most common affecting motor function and including resting tremor, rigidity, akinesia, bradykinesia and postural instability. Current pharmacological interventions are palliative and largely aimed at increasing dopamine levels through increased production and/or inhibition of metabolism of this key neurotransmitter. The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact. Consequently, as the number of substantia nigra dopamine neurons and striatal projections decrease, these treatments become less efficacious. Current translational research is focused on the development of novel disease-modifying therapies, including those utilizing gene therapeutic approaches. Herein we present an overview of current gene therapy clinical trials for Parkinson's disease. Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production; modulation of the neuronal phenotype; and neuroprotection. The first two therapies discussed in this article focus on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis (amino acid decarboxylase, tyrosine hydroxylase and GTP [guanosine triphosphate] cyclohydrolase 1). In an attempt to bypass the degenerating nigrostriatal pathway, a third clinical trial utilizes rAAV2 to deliver glutamic acid decarboxylase to the subthalamic nucleus, converting a subset of excitatory neurons to GABA-producing cells. In contrast, the final clinical trial is aimed at protecting the degenerating nigrostriatum by striatal delivery of rAAV2 harbouring the neuroprotective gene, neurturin. Based on preclinical studies, this gene therapeutic approach is posited to slow disease progression by enhancing neuronal survival. In addition, we discuss the outcome of each clinical trial and discuss the potential rationale for the marginal yet incremental clinical advancements that have thus far been realized for Parkinson's disease gene therapy.
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PMID:Gene therapy in Parkinson's disease: rationale and current status. 2015 94


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