Behavioral Recovery in 6-Hydroxydopamine-Lesioned Rats by Cotransduction of Striatum with Tyrosine Hydroxylase and Aromatic L-Amino Acid Decarboxylase Genes Using Two Separate Adeno-Associated Virus Vectors

Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

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“…Fan et al . [128] reported a similar result while using transduced TH and AADC in rat striatal cells, using two separate AAV vectors.…”

Section: Introductionmentioning

confidence: 67%

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Tabrez¹,

Jabir²,

Shakil³

et al. 2012

CNSNDDT

119

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“…IL-15 is known as a growth and survival factor for iNKT cells, 37, 38, 39 and we recently reported that IL-15 mRNA and protein levels are increased and correlate with esophageal eosinophilia in patients with EoE. 27 In order to further explore the relationship of IL-15 and iNKT cells in the pathogenesis of human EoE, we performed immunofluorescence staining on frozen proximal and distal esophageal biopsy sections of normal subjects and EoE patients, using an iNKT cell-specific receptor anti-hVα24Jα18 antibody (eBioscience, San Diego, CA, USA).…”

Section: Resultsmentioning

confidence: 99%

Invariant natural killer T‐cell neutralization is a possible novel therapy for human eosinophilic esophagitis

et al. 2014

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Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder that needs a potential therapeutic strategy. We earlier showed that iNKT cell-deficient mice are protected from allergen-induced EoE. Therefore, we now tested the hypothesis that iNKT cells are induced in the human EoE and is a novel possible target for the treatment of human EoE. Accordingly, we examine number of iNKT cells and eosinophils and expression of iNKT-associated cell surface receptors and chemokines by performing immunofluorescence, qPCR and ELISA in the esophageal biopsies and blood samples of normal subjects (comparison control) and EoE patients. Herein, we show that iNKT cell number, their receptor subcomponents Vα24 and Vβ11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals. In addition, we show that CXCL16 levels (or expression) correlate with the mRNA levels of Vα24 receptor but not well with esophageal eosinophilia in human EoE. Of note, we show that in vivo activation of iNKT cells is sufficient to induce EoE in mice. Furthermore, we show that anti-mCD1d- and anti-hVα24Jα18-neutralizing antibody treatment protects allergen-induced experimental EoE. Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Vα24Jα18 antibodies might be a novel and potential therapy for human EoE.

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“…The AAV co-transfection may raise concerns regarding efficiency of transgene expression from two mixed AAV vectors and injected into a single site. Fan et al showed that the tyrosine hydroxylase (TH) gene and also the aromatic L-amino acid decarboxylase (AADC) gene were simultaneously transduced into rat striatal cells via two separate AAV vectors, AAV-TH and AAV-AADC [33]. Immunostaining showed that TH and AADC were co-expressed efficiently in the same striatal cells in vitro and in vivo (>95% double-positive cells were counted).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of an AAV2-Based Rapamycin-Regulated Glial Cell Line-Derived Neurotrophic Factor (GDNF) Expression Vector System

et al. 2011

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Effective regulation of transgene product in anatomically circumscribed brain tissue is dependent on the pharmacokinetics of the regulating agent, the kinetics of transcriptional activation and degradation of the transgene product. We evaluated rapamycin-regulated AAV2-GDNF expression in the rat brain (striatum). Regulated (a dual-component system: AAV2-FBZhGDNF + AAV2-TF1Nc) and constitutive (CMV-driven) expression vectors were compared. Constitutively active AAV2-GDNF directed stable GDNF expression in a dose-dependent manner and it increased for the first month, thereafter reaching a plateau that was maintained over a further 3 months. For the AAV2-regGDNF, rapamycin was administered in a 3-days on/4-days off cycle. Intraperitoneal, oral, and direct brain delivery (CED) of rapamycin were evaluated. Two cycles of rapamycin at an intraperitoneal dose of 10 mg/kg gave the highest GDNF level (2.75±0.01ng/mg protein). Six cycles at 3 mg/kg resulted in lower GDNF values (1.36±0.3 ng/mg protein). Interestingly, CED of rapamycin into the brain at a very low dose (50 ng) induced GDNF levels comparable to a 6-week intraperitoneal rapamycin cycle. This study demonstrates the effectiveness of rapamycin regulation in the CNS. However, the kinetics of the transgene in brain tissue, the regulator dosing amount and schedule are critical parameters that influence the kinetics of accumulation and zenith of the encoded transgene product.

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Behavioral Recovery in 6-Hydroxydopamine-Lesioned Rats by Cotransduction of Striatum with Tyrosine Hydroxylase and Aromatic L-Amino Acid Decarboxylase Genes Using Two Separate Adeno-Associated Virus Vectors

Cited by 25 publications

References 22 publications

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Invariant natural killer T‐cell neutralization is a possible novel therapy for human eosinophilic esophagitis

Evaluation of an AAV2-Based Rapamycin-Regulated Glial Cell Line-Derived Neurotrophic Factor (GDNF) Expression Vector System

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