Improved Titers for Helper Virus-Free Herpes Simplex Virus Type 1 Plasmid Vectors by Optimization of the Packaging Protocol and Addition of Noninfectious Herpes Simplex Virus-Related Particles (Previral DNA Replication Enveloped Particles) to the Packaging Procedure

Sun, Minghan; Zhang, Guorong; Yang, Tianzhong; Yu, Linda Chia‐Hui; Geller, Alfred I.

doi:10.1089/10430349950017365

Cited by 46 publications

(61 citation statements)

References 36 publications

(27 reference statements)

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“…Similarly, a rat that received the 3-gene-vector contained FLAG-IR-or human AADC-IR-positive striatal cells (data not shown). Also, these results are consistent with earlier studies that delivered HSV-1 vectors into the striatum (During et al, 1994;Sun et al, 1999Sun et al, , 2003Zhang et al, 2000). Thus, the present analyses focused on the transfected striatal cells near the injection sites.…”

Section: Expression Of Dopamine Biosynthetic and Transporter Proteinssupporting

confidence: 92%

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Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Sun¹,

Kong²,

Wang³

et al. 2004

Human Gene Therapy

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Parkinson's disease is due to the selective loss of nigrostriatal dopaminergic neurons. Consequently, many therapeutic strategies have focused on restoring striatal dopamine levels, including direct gene transfer to striatal cells, using viral vectors that express specific dopamine biosynthetic enzymes. The central hypothesis of this study is that coexpression of four dopamine biosynthetic and transporter genes in striatal neurons can support the efficient production and regulated, vesicular release of dopamine: tyrosine hydroxylase (TH) converts tyrosine to L-3,4-dihydroxyphenylalanine (L -DOPA), GTP cyclohydrolase I (GTP CH I) is the rate-limiting enzyme in the biosynthesis of the cofactor for TH, aromatic amino acid decarboxylase (AADC) converts L -DOPA to dopamine, and a vesicular monoamine transporter (VMAT-2) transports dopamine into synaptic vesicles, thereby supporting regulated, vesicular release of dopamine and relieving feedback inhibition of TH by dopamine. Helper virus-free herpes simplex virus type 1 vectors that coexpress the three dopamine biosynthetic enzymes (TH, GTP CH I, and AADC; 3-gene-vector) or these three dopamine biosynthetic enzymes and the vesicular monoamine transporter (TH, GTP CH I, AADC, and VMAT-2; 4-gene-vector) were compared. Both vectors supported production of dopamine in cultured fibroblasts. These vectors were microinjected into the striatum of 6-hydroxydopamine-lesioned rats. These vectors carry a modified neurofilament gene promoter, and γ-aminobutyric acid (GABA)-ergic neuronspecific gene expression was maintained for 14 months after gene transfer. The 4-gene-vector supported higher levels of correction of apomorphine-induced rotational behavior than did the 3-gene-vector, and this correction was maintained for 6 months. Proximal to the injection sites, the 4-gene-vector, but not the 3-gene-vector, supported extracellular levels of dopamine and dihydroxyphenylacetic acid (DOPAC) that were similar to those observed in normal rats, and only the 4-gene-vector supported significant K + -dependent release of dopamine. OVERVIEW SUMMARY

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Section: Expression Of Dopamine Biosynthetic and Transporter Proteinssupporting

confidence: 92%

“…Vectors were packaged into HSV-1 particles, using the helper virus-free packaging system (Fraefel et al, 1996) as modified to improve the titers (Sun et al, 1999). Vector stocks were purified and concentrated as described .…”

Section: Vector Packagingmentioning

confidence: 99%

Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Sun¹,

Kong²,

Wang³

et al. 2004

Human Gene Therapy

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“…The growth of baby hamster kidney fibroblast (BHK21) cells [40] and 2-2 cells [36] has been described.…”

Section: Cellsmentioning

confidence: 99%

“…Helper virus-free packaging [8] was performed using a modified protocol [40] that improves the efficiency. 2-2 cells were cotransfected with a vector and an HSV-1 cosmid set that lacked a packaging site (cos6Δa, cos14, cos28, cos48Δa, and each of the three cos56 (containing the gC-GDNF chimeric gene, or the gC-BDNF chimeric gene, or wt gC)).…”

Section: Vector Packaging and Titeringmentioning

confidence: 99%

“…GDNF is a secreted protein that contains a signal sequence [25] to support proper posttranslational processing, and the gC deletion retains the transmembrane domain to support insertion into the envelope of HSV-1 particles. (c) Helper virus-free packaging [8,40] was performed using this chimeric gC-GDNF construct. An HSV-1 vector and an HSV-1 cosmid set that contained the chimeric gC-GDNF construct and lacked an a sequence (contains the packaging site) were cotransfected into 2-2 cells [36].…”

Section: Implications For Physiological Studiesmentioning

confidence: 99%

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Targeted gene transfer to nigrostriatal neurons in the rat brain by helper virus-free HSV-1 vector particles that contain either a chimeric HSV-1 glycoprotein C-GDNF or a gC-BDNF protein

Wang¹,

Kong²,

Zhang³

et al. 2005

Molecular Brain Research

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Direct gene transfer into neurons has potential for both studying neuronal physiology and for developing gene therapy treatments for specific neurological conditions. Due to the heterogeneous cellular composition of the brain, cell-type-specific recombinant gene expression is required for many potential applications of neuronal gene transfer. The two prevalent approaches for achieving celltype-specific expression are to use a cell-type-specific promoter to control recombinant gene expression or to modify a virus vector particle to target gene transfer to a specific cell type. Targeted gene transfer to multiple peripheral cell types has been described, but targeted gene transfer to a specific type of neuron in the brain has yet to be reported. Targeted gene transfer approaches with Herpes Simplex Virus (HSV-1) vectors have focused on modifying glycoprotein C (gC) to remove the heparin binding domain and add a binding activity for a specific protein on the cell surface. This study was designed to develop HSV-1 vectors that target gene transfer to cells that contain receptors for either glial-cell-line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF), such as nigrostriatal neurons. We isolated chimeric gC-GDNF or chimeric gC-BDNF constructs, and the resulting proteins were incorporated into HSV-1 virus particles. We performed helper virus-free HSV-1 vector packaging in the presence of each chimeric protein. The resulting vector stocks supported 2.2-to 5.0-fold targeted gene transfer to nigrostriatal neurons in the rat brain, compared to vector particles that contained wild-type (wt) gC. Gene transfer to nigrostriatal neurons by vector particles that contained chimeric gC-BDNF was reduced by preincubation with an anti-BDNF antibody. Targeted gene transfer to neurons that contain specific neurotrophic factor receptors may benefit specific physiological and gene therapy studies.

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Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons

Zhang¹,

Li²,

Kong³

et al. 2008

Hippocampus

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Age-related declines in human cognition are well known, and there are correlative changes in the function of neocortical and hippocampal neurons. Similarly, age-related declines in learning have been observed in rodents, including deficits in a hippocampal-dependent learning paradigm, the Morris water maze. Furthermore, there are correlative deficits in specific signaling pathways, including protein kinase C (PKC) pathways, in cerebellar, hippocampal, or neocortical neurons. PKC pathways are strong candidates for mediating the molecular changes that underlie spatial learning, as they play critical roles in neurotransmitter release and synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), and deletion of specific PKC genes results in deficits in learning. Conversely, genetic activation of PKC pathways in small groups of hippocampal or cortical neurons enhances learning in specific paradigms. In this study, we delivered a constitutively active PKC into small groups of hippocampal dentate granule neurons in aged rats (using a Herpes Simplex Virus-1 vector). Aged two-year old rats that received the constitutively active PKC displayed improved performance in the Morris water maze relative to controls in three different measures. These results indicate that PKC pathways play an important role in mediating spatial learning in aged rats. Additionally, these results represent a system for studying the neural mechanisms underlying aging-related learning deficits, and potentially developing gene therapies for cognitive and age-related deficits.

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Improved Titers for Helper Virus-Free Herpes Simplex Virus Type 1 Plasmid Vectors by Optimization of the Packaging Protocol and Addition of Noninfectious Herpes Simplex Virus-Related Particles (Previral DNA Replication Enveloped Particles) to the Packaging Procedure

Cited by 46 publications

References 36 publications

Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Targeted gene transfer to nigrostriatal neurons in the rat brain by helper virus-free HSV-1 vector particles that contain either a chimeric HSV-1 glycoprotein C-GDNF or a gC-BDNF protein

Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons

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