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Joseph C Glorioso

Publications and source records attributed to Joseph C Glorioso.

At least 37 records · Page 2Linked to original sources
PubMed2004

Protective effect of herpes simplex virus-mediated neurotrophin gene transfer in cisplatin neuropathy.

Attempts to develop clinical treatments for neuropathy using neurotrophins have not been successful. We tested whether neurotrophin gene delivery to dorsal root ganglia (DRGs) using non-replicating herpes simplex virus (HSV)-based vectors could prevent the development of neuropathy caused by administration of cisplatin. Following subcutaneous inoculation of HSV vectors expressing nerve growth factor (NGF) or neurotrophin-3 (NT-3), neurons in the DRG were transduced to produce NGF or NT-3 in vivo. Inoculation of either the NGF- or the NT-3-expressing vectors 3 days before the start of a 6-week course of cisplatin treatment protected against cisplatin-induced neuropathy assessed by electrophysiological, histological and behavioural measures 2 months later. Iatrogenic neuropathy caused by administration of chemotherapeutic drugs represents an excellent target for a human trial to assess the potential of gene therapy to prevent neuropathy.

Animals↗
PubMed2004

Structural and functional features of the polycationic peptide required for inhibition of herpes simplex virus invasion of cells.

Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) mediates initial virus contact with cells by binding to heparan sulfate (HS) chains. The synthetic peptide 137GSRVQIRCRFRNSTR151 overlapping a major part of the HS-binding site of gC inhibited HSV-1 infection and, to some extent, HSV-2 infection of cells. Experiments on mutant, glycosaminoglycan-deficient cells as well as the binding assays involving peptide and purified cell surface components identified HS, and, to a lesser degree, chondroitin sulfate as sites of peptide activity. Anti-HSV-1 activity of the peptide was due to (i) partial inhibition of virus binding to cells and (ii) arresting the virions, which managed to attach to the cells in the presence of peptide, at a step of initial relatively weak binding. Analysis of the ionic-strength dependence of the peptide-HS and the virus-HS interactions revealed that the more efficient inhibition by the peptide of HSV-1 than HSV-2 infectivity was due to a relatively high affinity of HSV-2 for HS, a feature of importance in overcoming the peptide block. Mutational analysis of viral gC and peptide variants identified, apart from basic amino acids, two hydrophobic residues Ile(142) and Phe(146) as important in maintaining the specific affinity of peptide for HS and, hence, its anti-HSV activity. These results could contribute to the development of anti-HSV compounds that target initial events in the virus-cell interaction.

Animals↗
PubMed2004

Prolonged biologically active transgene expression driven by HSV LAP2 in brain in vivo.

Herpes simplex virus (HSV) naturally establishes a life-long latent state in neurons, characterized by the expression of latency-associated transcripts (LATs) in the absence of viral lytic functions, and the latency-associated promoter (LAP2) has been identified as a moveable element responsible for the expression of LATs from latent HSV genomes. Prolonged transgene expression will be required for the treatment of chronic diseases of the CNS using HSV vectors. We therefore examined the ability of LAP2 to drive prolonged expression of a biologically active transgene from latent HSV vector genomes in brain in vivo using the 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of Parkinson disease. A replication-incompetent HSV vector containing the glial cell-derived neurotrophic factor (GDNF) under the control of LAP2 was injected into the substantia nigra and 5 and a half months later 6-OHDA was injected into the striatum. GDNF expression from the vector preserved dopaminergic function measured by histology and behavior 6 months after vector inoculation. Mice inoculated with the LAP2-GDNF replication-incompetent HSV vector followed by 3 months of daily low-dose MPTP injections were substantially protected against the consequences of that treatment measured by weekly behavioral testing and histologic measures at the conclusion of the experiment. These studies using subacute and chronic models of neurodegeneration demonstrate that the HSV LAP2 promoter element provides prolonged expression of relevant amounts of a transgene to produce significant biological effects in brain in vivo over the course of many months.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain.

Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of gamma-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.

Animals↗
PubMed2004

Immobilized cobalt affinity chromatography provides a novel, efficient method for herpes simplex virus type 1 gene vector purification.

Herpes simplex virus type 1 (HSV-1) is a promising vector for gene therapy applications, particularly at peripheral nerves, the natural site of virus latency. Many gene vectors require large particle numbers for even early-phase clinical trials, emphasizing the need for high-yield, scalable manufacturing processes that result in virus preparations that are nearly free of cellular DNA and protein contaminants. HSV-1 is an enveloped virus that requires the development of gentle purification methods. Ideally, such methods should avoid centrifugation and may employ selective purification processes that rely on the recognition of a unique envelope surface chemistry. Here we describe a novel method that fulfills these criteria. An immobilized metal affinity chromatography (IMAC) method was developed for the selective purification of vectors engineered to display a high-affinity binding peptide. Feasibility studies involving various transition metal ions (Cu2+, Zn2+, Ni2+, and Co2+) showed that cobalt had the most desirable features, which include a low level of interaction with either the normal virus envelope or contaminating DNA and proteins. The introduction of a cobalt-specific recognition element into the virus envelope may provide a suitable target for cobalt-dependent purification. To test this possibility, we engineered a peptide with affinity for immobilized cobalt in frame in the heparan sulfate binding domain of HSV-1 glycoprotein B, which is known to be exposed on the surface of the virion particle and recombined into the viral genome. By optimizing the IMAC loading conditions and reducing cobalt ion leakage, we recovered 78% of the tagged HSV-1 recombinant virus, with a >96% reduction in contaminating proteins and DNA.

Adsorption↗
PubMed2004

Herpes vector-mediated gene transfer in treatment of diseases of the nervous system.

Vectors constructed from recombinant herpes simplex virus (HSV) have special utility for gene transfer to the nervous system. Nonreplicating vectors created by deletion of essential immediate early genes can be propagated to high titers on complementing cell lines that provide the missing gene product(s) in trans. Direct inoculation of these vectors into neural parenchyma is effective in rodent models of brain tumor, Parkinson disease, spinal cord injury, and spinal root trauma. Subcutaneous inoculation of the HSV vectors can be used to transduce neurons of the dorsal root ganglion to provide a therapeutic effect in models of polyneuropathy and chronic regional pain. In human trials, direct injection of replication-competent HSV into brain tumors has proven safe. Human trials of nonreplicating HSV gene transfer by direct inoculation for treatment of glioblastoma and HSV gene transfer by subcutaneous inoculation for the treatment of chronic intractable pain should commence soon.

Animals↗
PubMed2004

Delivery using herpes simplex virus: an overview.

The human herpesviruses represent excellent candidate viruses for several types of gene vector applications. As a class, they are large DNA viruses with the potential to accommodate large or multiple transgene cassettes, and they have evolved to persist in a lifelong nonintegrated latent state without causing disease in the immune-competent host. Among the herpesviruses, herpes simplex virus type 1 (HSV-1) is an attractive vehicle because in natural infection, the virus establishes latency in neurons, a state in which viral genomes may persist for the life of the host as intranuclear episomal elements. The natural lifelong persistence of latent genomes in trigeminal ganglia (TG) without the development of sensory loss or histologic damage to the ganglion attests to the effectiveness of these natural latency mechanisms. Although the wild-type virus may be reactivated from latency under the influence of a variety of stresses, completely replication defective viruses can be constructed that retain the ability to establish persistent quiescent genomes in neurons, but that are unable to subsequently reactivate in the nervous system. These persistent genomes are devoid of lytic gene expression, but retain the ability to express latency-associated transcripts (LATs).

Animals↗
PubMed2004

Delivery of herpes simplex virus-based vectors to the nervous system.

Gene transfer to the nervous system is an attractive option to treat a wide variety of neurological insults. The expression of trophic factor and/or antiapoptotic genes may be beneficial in halting the slow neurodegeneration in such conditions as Parkinson's disease (4,5), the rapid neuronal cell death following trauma to the brain or spinal cord (6,7), or in treating peripheral neuropathies associated with diabetes or use of chemotherapeutic agents (8,9). Introduction of dominant-negative mutant genes or antisense RNA to treat diseases such as Huntington's disease, or transfer of genes to replace lost or mutated endogenous proteins to treat disorders such as lysosomal storage diseases, may prove useful. In addition, gene transfer to overexpress endogenous antinociceptive proteins has great potential in pain management. The problem faced by all of these applications is finding a suitable methodology that will facilitate the transfer of exogenous genes to the appropriate nerve cells; virusbased vectors have proven quite efficient in transferring genes to many different cell types.

Animals↗
PubMed2004

Gene transfer to glial tumors using herpes simplex virus.

Glial tumors occur as intraaxial masses in the brain and are uniformly fatal due to lack of effective therapy. Resection combined with radiation and chemotherapy fails to eradicate malignant cells infiltrating into normal brain, and recurrence at the original site is ultimately fatal. Gene transfer offers the potential to enhance tumor cell killing while sparing surrounding normal brain. Several approaches have been developed to deliver genes to tumor cells in order to kill these cells. The first strategy involves the use of viral vectors that are replication-competent, but depend on attributes unique to the tumor cell to support viral growth. Both replication-competent adenovirus and herpes simplex virus (HSV) vectors have been employed in pre-clinical studies and most recently in human clinical trials. For this purpose, HSV vectors have been engineered that replicate in dividing cells, such as tumor cells, but not in normal neurons. The use of conditional replication competent viruses could allow for their spread in tumor tissue while minimizing damage to normal brain, thus increasing the specificity and effectiveness. Such mutants include those lacking the viral thymidine kinase (tk) gene (4-7), ribonucleotide reductase gene (8,9), a protein kinase gene, or a gene (gamma34.5) required for growth specifically in neurons (11-13).

Animals↗
PubMed2004

Delivery of herpes simplex virus-based vectors to stem cells.

In contrast to traditional drugs that generally act by altering existing gene product function, gene therapy aims to target the root cause of the disease by altering the genetic makeup of the cell to treat the disease. Researchers have adapted several classes of viruses as gene-transfer vectors, taking advantage of natural viral mechanisms designed to efficiently and effectively deliver DNA to the host-cell nucleus. Among these, the human herpesviruses are excellent candidate vectors for a variety of applications. Herpes simplex virus type 1 (HSV-1) is a particularly attractive gene-transfer vehicle because natural infection in humans includes a latent state in which the viral genome persists in a nonintegrated form without causing disease in an immune-competent host. HSV-1 is a large DNA virus with a broad host range that can be engineered to accommodate multiple or large therapeutic transgenes (4). HSV vectors may be generally useful for gene transfer to a variety of tissues in which short-term or extended transgene expression of therapeutic transgenes achieve a therapeutic effect. We have used therapeutic vectors to successfully treat human disease models in animals, including cancer, Parkinson's disease, and nerve damage (5-10).

Animals↗
PubMed2004

Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy.

Diabetic cystopathy is one of the common complications of diabetes and current therapy is limited. In the present study, the effects of gene therapy, using replication-defective herpes simplex virus type 1 (HSV-1) vectors to deliver and express the nerve growth factor (NGF) gene (HSV-NGF) on tissue NGF levels and bladder function, were evaluated in streptozotocin (STZ)-induced diabetic rats. Diabetic rats exhibited a significant decrease in NGF levels in the bladder and lumbosacral dorsal root ganglia (DRG) detected by enzyme-linked immunosorbent assay and displayed marked bladder dysfunction 12 weeks after STZ injection. In contrast, rats with bladder wall injection of the NGF expression vector 8 weeks after STZ treatment exhibited a significant increase of NGF levels in the bladder and L6 DRG 4 weeks after HSV-NGF injection. Along with the restoration of tissue NGF expression, in metabolic cage studies and cystometry, HSV-NGF-injected rats also showed significantly reduced bladder capacity and postvoid residual volume than diabetic rats injected with the control vector (HSV-lacZ), indicating that voiding function was improved after HSV vector-mediated NGF gene delivery. Thus, HSV vector-mediated NGF gene therapy may prove useful to restore decreased NGF expression in the bladder and bladder afferent pathways, thereby improving hypoactive bladder function in diabetes.

Animals↗
PubMed2003

Cell and gene therapy in the treatment of pain.

Chronic pain represents a clinical problem of enormous impact. Understanding of the anatomy, pharmacology, and physiology of pain has resulted in the identification of new targets and candidate drugs, but effective novel therapies have been slow to emerge. One approach is to transplant cells that secrete bioactive macromolecules, or use viral vectors to transfer the genes coding for those molecules, in order to deliver short-lived potent peptides of known analgesic efficacy to targeted sites in the nervous system. The data from animal models are reviewed, and the prospect for development of human therapies based on this approach is considered.

Adenoviridae↗
PubMed2003

Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees.

To examine the effect of transforming growth factor (TGF)-beta1 on the regulation of cartilage synthesis and other articular pathologies, we used adenovirus-mediated intra-articular gene transfer of TGF-beta1 to both naïve and arthritic rabbit knee joints. Increasing doses of adenoviral vector expressing TGF-beta1 were injected into normal and antigen-induced arthritis rabbit knee joints through the patellar tendon, with the same doses of an adenoviral vector expressing luciferase injected into the contralateral knees as the control. Intra-articular injection of adenoviral vector expressing TGF-beta1 into the rabbit knee resulted in dose-dependent TGF-beta1 expression in the synovial fluid. Intra-articular TGF-beta1 expression in both naïve and arthritic rabbit knee joints resulted in significant pathological changes in the rabbit knee as well as in adjacent muscle tissue. The observed changes induced by elevated TGF-beta1 included inhibition of white blood cell infiltration, stimulation of glycosaminoglycan release and nitric oxide production, and induction of fibrogenesis and muscle edema. In addition, induction of chondrogenesis within the synovial lining was observed. These results suggest that even though TGF-beta1 may have anti-inflammatory properties, it is unable to stimulate repair of damaged cartilage, even stimulating cartilage degradation. Gene transfer of TGF-beta1 to the synovium is thus not suitable for treating intra-articular pathologies.

Adenoviridae↗
PubMed2003

Enhanced functional recovery after proximal nerve root injury by vector-mediated gene transfer.

In order to test the functional implication of herpes simplex virus (HSV) vector-mediated gene transfer after axonal injury, we injected replication-incompetent HSV vectors coding for the anti-apoptotic peptide Bcl-2 and the glial cell-derived neurotrophic factor (GDNF), separately or in combination into ventral spinal cord 30 min after a crush injury to the proximal spinal root that was combined with moderate mechanical traction. HSV-mediated expression of Bcl-2 or GDNF enhanced functional recovery assessed by histologic, electrophysiologic, and behavioral parameters up to 5 months after injury. The most sensitive measure of distal motor function, the sciatic function index, was significantly improved in animals injected with the two vectors together. These results suggest an approach to root trauma that might be used to enhance functional recovery after injury.

Animals↗
PubMed2003

In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL, HCL, B-CLL).

A replication defective herpes simplex virus-1 was evaluated as a therapeutic vector. Mantle cell lymphoma (MCL), hairy cell leukemia (HCL), and B-cell chronic lymphocytic leukemia (B-CLL) were chosen because leukemic cells were collectable from peripheral bloods in these diseases. Cells from six MCL, one HCL, and nine B-CLL were infected in vitro with T0Z.1 at 3 multiplicity of infection (MOI). Herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV)-mediated suicide gene therapy showed 14.7% of mean tumor killing against leukemic B-cell malignancies. The mean tumor-killing effects were 8.7 and 17.1% in MCL and B-CLL, respectively. The effect against HCL was 29%. The study indicates that herpes simplex virus (HSV)-based gene therapy might be an effective strategy.

Adult↗
PubMed2003

Transgene-mediated enkephalin release enhances the effect of morphine and evades tolerance to produce a sustained antiallodynic effect in neuropathic pain.

We examined the pharmacologic characteristics of herpes simplex virus (HSV) vector-mediated expression of proenkephalin in the dorsal root ganglion in a rodent model of neuropathic pain. We found that: (i). vector-mediated enkephalin produced an antiallodynic effect that was reversed by naloxone; (ii). vector-mediated enkephalin production in animals with spinal nerve ligation prevented the induction of c-fos expression in second order sensory neurons in the dorsal horn of spinal cord; (iii). the effect of vector-mediated enkephalin enhanced the effect of morphine, reducing the ED(50) of morphine 10-fold; (iv). animals did not develop tolerance to the continued production of vector-mediated enkephalin over a period of several weeks; and, (v). vector transduction continued to provide an analgesic effect despite the induction of tolerance to morphine. This is the first demonstration of gene transfer to provide an analgesic effect in neuropathic pain. The pharmacologic analysis demonstrates that transgene-mediated expression and local release of opioid peptides produce some effects that are distinct from peptide analogues delivered pharmacologically.

Animals↗
PubMed2003

Gene transfer of human manganese superoxide dismutase protects small intestinal villi from radiation injury.

Small bowel toxicity represents a major dose-limiting side effect of radiation treatment for many malignancies. We examined the effects of overexpressing human manganese superoxide dismutase (MnSOD) in the small intestine in mice to prevent radiation enteritis. Mice were treated with the human MnSOD gene delivered enterally using a nontoxic, replication-defective herpes simplex virus (HSV)-1-based vector. HSV vectors containing the human MnSOD transgene and green fluorescent protein (GFP) transgene, or GFP transgene alone, were constructed and injected intraluminally into a 2cm length of small intestine of C3H/HeNsd mice. Total body irradiation of 15 Gy was delivered to mice inoculated 24 hours earlier with either HSV-MnSOD (10(3) to 10(8) plaque-forming units), control HSV-GFP, or no vector. At 24 or 72 hours after irradiation, mice were killed and villi areas were measured from appropriate segments of the small intestine. Control irradiated mice showed a decreased villi area of 82% by day 3 after irradiation, whereas treatment of mice with HSV-MnSOD 10(8) plaque-forming units led to only a 16% decrease in villi area (P < 0.001) before radiation. Similar findings were seen on day 3 and were associated with a significant (P < 0.001) preservation of enteric protein content in HSV-MnSOD-treated mice. A dose-dependent effect of MnSOD in preventing radiation-induced small bowel injury was evident. These data demonstrate that overexpression of human MnSOD via a replication-defective herpes viral vector is an efficacious method of protecting the small intestine from ionizing radiation damage.

Analysis of Variance↗