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

Several neurological diseases which affect the corpus striatum are candidates for gene therapy. We have developed a defective Herpes Simplex Virus (HSV-1) vector system to introduce genes into postmitotic cells, such as neurons. The prototype vector, pHSVlac, contains a transcription unit which places the E. coli Lac Z gene under the control of the HSV-1 immediate early (IE) 4/5 promoter, a constitutive promoter. We now demonstrate that a HSV-1 vector can deliver a gene into striatal neurons. Infection of cultured rat striatal neurons with pHSVlac virus resulted in stable expression of beta-galactosidase for at least two weeks, without cell death. The potential to replace the Lac Z gene with other genes of interest, such as the gene responsible for Huntington's Disease, once it is isolated, may lead to insights about the pathogenesis of this genetic neurodegenerative disease, and may provide a method for performing gene therapy on this disease. Similarly, introduction of the tyrosine hydroxylase gene, which encodes the rate-limiting enzyme in the conversion of tyrosine to dopamine, into striatal neurons might provide a novel gene therapy approach towards treating Parkinson's Disease.
 ...
PMID:Infection of cultured striatal neurons with a defective HSV-1 vector: implications for gene therapy. 166 13

We have previously described a defective herpes simplex virus (HSV-1) vector system that permits the introduction of virtually any gene into nonmitotic cells. pHSVlac, the prototype vector, stably expresses Escherichia coli beta-galactosidase from a constitutive promoter in many human cell lines, in cultured rat neurons from throughout the nervous system, and in cells in the adult rat brain. HSV-1 vectors expressing other genes may prove useful for studying neuronal physiology or performing human gene therapy for neurological diseases, such as Parkinson disease or brain tumors. A HSV-1 temperature-sensitive (ts) mutant, ts K, has been used as helper virus; ts mutants revert to wild type. In contrast, HSV-1 deletion mutants essentially cannot revert to wild type; therefore, use of a deletion mutant as helper virus might permit human gene therapy with HSV-1 vectors. We now report an efficient packaging system for HSV-1 vectors using a deletion mutant, D30EBA, as helper virus; virus is grown on the complementing cell line M64A. pHSVlac virus prepared using the deletion mutant packaging system stably expresses beta-galactosidase in cultured rat sympathetic neurons and glia. Both D30EBA and ts K contain a mutation in the IE3 gene of HSV-1 strain 17 and have the same phenotype; therefore, changing the helper virus from ts K to D30EBA does not alter the host range or other properties of the HSV-1 vector system.
 ...
PMID:An efficient deletion mutant packaging system for defective herpes simplex virus vectors: potential applications to human gene therapy and neuronal physiology. 217 68

Adeno-associated viral (AAV) vectors are non-pathogenic, integrating DNA vectors in which all viral genes are removed and helper virus is completely eliminated. To evaluate this system in the post-mitotic cells of the brain, we found that an AAV vector containing the lacZ gene (AAVlac) resulted in expression of beta-galactosidase up to three months post-injection in vivo. A second vector expressing human tyrosine hydroxylase (AAVth) was injected into the denervated striatum of unilateral 6-hydroxydopamine-lesioned rats. Tyrosine hydroxylase (TH) immunoreactivity was detectable in striatal neurons and glia for up to four months and we also found significant behavioural recovery in lesioned rats treated with AAVth versus AAVlac controls. Safe and stable TH gene transfer into the denervated striatum may have potential for the genetic therapy of Parkinson's disease.
 ...
PMID:Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. 784 13

Transgenic (NFHLacZ) mice expressing a fusion protein composed of a truncated high-molecular-weight mouse neurofilament (NF) protein (NFH) fused to beta-galactosidase (LacZ) develop inclusions in neurons throughout the CNS. These inclusions persist from birth to advanced age and contain massive filamentous aggregates including all three endogenous NF proteins and the NFHLacZ fusion protein. Further, the levels of endogenous NF proteins are selectively reduced in NFHLacZ mice. Because these inclusions resemble NF-rich Lewy bodies (LBs) in Parkinson's disease and LB dementia, we asked whether these lesions compromised the viability of affected neurons during aging. We studied hippocampal CA1 neurons, nearly all of which harbored inclusions (type I) devoid of cellular organelles, and cerebellar Purkinje cells, nearly all of which accumulated inclusions (type II) containing numerous entrapped organelles. Purkinje cells with type II inclusions began to degenerate in the NFHLacZ mice at approximately 1 year of age, and most were eliminated by 18 months of age. In contrast, there was no significant loss of type I inclusion-bearing CA1 neurons with age. These data suggest that the sequestration of cellular organelles in type II inclusions may isolate and impair the function of these organelles, thereby rendering Purkinje cells selectively vulnerable to degeneration with age as in neurodegenerative diseases of the elderly characterized by accumulation of LBs.
 ...
PMID:Selective degeneration fo Purkinje cells with Lewy body-like inclusions in aged NFHLACZ transgenic mice. 899 61

Current approaches to gene therapy of CNS disorders include grafting genetically modified autologous cells or introducing genetic material into cells in situ using a variety of viral or synthetic vectors to produce and deliver therapeutic substances to specific sites within the brain. Here we discuss issues related to the application of ex-vivo and in-vivo gene therapies as possible treatments for Parkinson's disease. Autologous monkey fibroblasts engineered ex-vivo to express tyrosine hydroxylase were grafted into MPTP-treated monkeys and found to express for up to 4 months. Adeno-associated (AAV) viral vectors expressing beta-galactosidase or tyrosine hydroxylase were introduced into monkey brains to determine the extent of infection and the types of cells infected by the vector at 21 days and 3 months. Gene expression was detected at both time points and was restricted to neurons in the striatum. These experiments demonstrate that two different approaches can be used to deliver proteins into the CNS. However, further technological advances are required to optimize gene delivery, regulation of gene expression, and testing in appropriate functional models before gene therapy can be considered for treating human disease.
 ...
PMID:Practical aspects of the development of ex vivo and in vivo gene therapy for Parkinson's disease. 912 64

Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and beta-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.
 ...
PMID:Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase. 915 52

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for adult nigral dopamine neurons in vivo. GDNF has both protective and restorative effects on the nigro-striatal dopaminergic (DA) system in animal models of Parkinson disease. Appropriate administration of this factor is essential for the success of its clinical application. Since it cannot cross the blood-brain barrier, a gene transfer method may be appropriate for delivery of the trophic factor to DA cells. We have constructed a recombinant adenovirus (Ad) encoding GDNF and injected it into rat striatum to make use of its ability to infect neurons and to be retrogradely transported by DA neurons. Ad-GDNF was found to drive production of large amounts of GDNF, as quantified by ELISA. The GDNF produced after gene transfer was biologically active: it increased the survival and differentiation of DA neurons in vitro. To test the efficacy of the Ad-mediated GDNF gene transfer in vivo, we used a progressive lesion model of Parkinson disease. Rats received injections unilaterally into their striatum first of Ad and then 6 days later of 6-hydroxydopamine. We found that mesencephalic nigral dopamine neurons of animals treated with the Ad-GDNF were protected, whereas those of animals treated with the Ad-beta-galactosidase were not. This protection was associated with a difference in motor function: amphetamine-induced turning was much lower in animals that received the Ad-GDNF than in the animals that received Ad-beta-galactosidase. This finding may have implications for the development of a treatment for Parkinson disease based on the use of neurotrophic factors.
 ...
PMID:Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease. 923 61

Tyrosinase and tyrosinase-related proteins (TRP-1 and TRP-2) are essential for melanin synthesis and are expressed in neural crest-derived melanocytes and in the pigment epithelium of the retina. Recent results suggest expression of all three proteins within the central nervous system. We performed a transgenic assay using beta-galactosidase as reporter gene to monitor tyrosinase promoter activity in vivo. During embryogenesis, we found expression in several locations of developing forebrain and midbrain. Tyrosinase, TRP-1 and TRP-2 had been equally found in extracts of adult mouse brain. In adult brain, we detected tyrosinase promoter activity in cortex, olfactory system, hippocampus, epithalamus and substantia nigra, areas corresponding to positive staining during embryogenesis. Thus, tyrosinase promoter is active throughout murine brain development, and tyrosinase could be implicated in neuromelanin formation in the substantia nigra, and in neurodegenerative disorders like Parkinson's disease.
 ...
PMID:New evidence for presence of tyrosinase in substantia nigra, forebrain and midbrain. 947 5

An adeno-associated virus (AAV) vector, expressing genes for human tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), demonstrated significantly increased production of dopamine in 293 (human embryonic kidney) cells. This bicistronic vector was used to transduce striatal cells of six asymptomatic but dopamine-depleted monkeys which had been treated with the neurotoxin MPTP. Striatal cells were immunoreactive for the vector-encoded TH after stereotactic injection for periods up to 134 days, with biochemical effects consistent with dopamine biosynthetic enzyme expression. A subsequent experiment was carried out in six more severely depleted and parkinsonian monkeys. Several TH/aadc-treated monkeys showed elevated levels of dopamine near injection tracts after 2.5 months. Two monkeys that received a beta-galactosidase expressing vector showed no change in striatal dopamine. Behavioral changes could not be statistically related to the vector treatment groups. Toxicity was limited to transient fever in several animals and severe hyperactivity in one animal in the first days after injection with no associated histological evidence of inflammation. This study shows the successful transfection of primate neurons over a period up to 2.5 months with suggestive evidence of biochemical phenotypic effects and without significant toxicity. While supporting the idea of an in vivo gene therapy for Parkinson's disease, more consistent and longer lasting biochemical and behavioral effects will be necessary to establish the feasibility of this appraoch in a primate model of parkinsonism.
 ...
PMID:In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. 974 62

Astrocytes are potentially useful as vehicles for gene transfer into the CNS. As endogenous CNS cells, they possess secretory mechanisms and can be grown in vitro. We have developed an animal model of this system using autologous astrocyte grafts in Fischer 344 rats. Cultured cells were infected with an adenoviral vector containing the reporter gene lacZ in vitro and then grafted into the striatum of adult Fischer 344 rats previously lesioned with 6-OHDA. Survival of the cells and activity of the beta-galactosidase protein were followed for up to 21 days after injection. The grafted cells were shown to survive throughout the experimental period although the expression of transgene was reduced with time. If long-term expression of therapeutically active substances can be achieved, grafts of adult-derived astrocytes genetically engineered using recombinant adenoviral vectors could be employed in the treatment of Parkinson's disease and other neurological disorders.
 ...
PMID:Survival of genetically engineered, adult-derived rat astrocytes grafted into the 6-hydroxydopamine lesioned adult rat striatum. 987 82


1 2 3 4 Next >>