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Joseph C. Glorioso III, Ph.D.
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Professor
E1253 BSTWR
200 Lothrop Street
Pittsburgh, Pennsylvania 15261
Phone: (412) 648-8105
Fax: (412) 624-8997
E-mail: glorioso@pitt.edu
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Biography
Dr. Glorioso is world-renowned for his work on the molecular and genetic aspects of the herpes simplex virus and how to better engineer this organism as a vector for transporting therapeutic genes. As previous chairman of the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine, he has attracted numerous high-profile investigators who are pursuing groundbreaking studies on a wide range of biological activities at the molecular level. Through Dr. Glorioso’s initiative, the department has gained an international reputation for its expertise in engineering and applying different viral vector systems for gene therapy. Scientists there hold nearly $16 million in funding for investigations into the genetics of and gene therapy for muscular dystrophy, arthritis, inherited metabolic disorders, chronic pain, cancer, juvenile diabetes and cardiovascular disease.
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Research
Herpes simplex virus type 1 (HSV-1) is a common human pathogen that often infects individuals at an early age. The virus is spread by direct contact with an active lesion. The virus replicates in the skin or mucus membrane epithelium and spreads to sensory nerve terminals. The virus is transported to sensory nerve bodies within the sensory ganglia where viral latency is established that persists for life. Virus activation from latency can occur as a result of nerve damage or immunosuppression thereby providing a mechanism for further virus transmission. Recurrent lesions occur at the original site of infection. HSV latent infections do not damage neurons.
The virus receptor interactions that allow infection to proceed and those that subsequently support the establishment of virus latency exclusively in neurons have been under study in my laboratory. The principle approaches used in my lab are molecular genetic and biochemical in nature and involve the manipulation of the virus genome through mutagenesis of specific viral functions. Comparative studies of wild type and mutant gene product behaviors provide powerful tools to relate their functional properties with specific biological activities. As examples, we have explored the role of DNA repair signaling pathways in the establishment of latency and the coordinated interactions among four envelope glycoproteins in mediating membrane fusion and virus entry into susceptible host cells.
Based on fundamental studies of these aspects of the virus biology, my laboratory has also developed experimental methods for engineering HSV as a gene transfer vector for delivery and expression of therapeutic genes in neurons, and include methods for vector retargeting to novel receptors. The vectors are replication defective and noncytoxix and they are incapable of latency reactivation. These vectors nevertheless persist in neurons in a latency-like state. Sensory neurons thus provide an ideal site for virus delivery of locally acting products that influence sensory nerve function and viability. Vector mediated delivery of individual genes or gene combinations have been used in treatment of preclinical models of cancers of the nervous system, chronic pain, and various neurodegenerative conditions. The treatment of recurrent glioblastoma and chronic pain due to cancer and diabetes are moving into phase 1 clinical trials with in the next 12 months now that the manufacturing processes and preclinical trials has now been completed. The gene therapy research tool and methods are protected by issued patents to the University of Michigan and the University of Pittsburgh. Future disease targets include the treatment of peripheral nerve damage from cancer, surgery or metabolic disease. For example, phase 1 trials to treat diabetic neuropathy are in the planning stages.
Finally, my laboratory has moved in the direction of using HSV vectors for studies of cellular gene functions and for analysis of embryonic stem cell differentiation using mouse, frog, and fish models. HSV vectors carrying complex CDNA libraries are being exploited in combination with powerful high through out read-out systems that can be coupled with chemical screens are in the planning stages. These new technologies should substantially change the way gene functions are discovered and dissected. Among target functions of interest, we are now (i) searching for cellular functions that control calcium channel signaling (E.G. the vanilloid receptor family of channels) in sensitizing nociceptor neurons to abnormal sensitivities to pain stimulators and (ii) searching for novel gene functions that control skeletal muscle development.
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Selected Publications
- Goss JR, Gold MS, Glorioso JC. 2009. "HSV vector-mediated modification of primary nociceptor afferents: an approach to inhibit chronic pain" Gene Ther. 16:493-501. | Abstract
- Grandi P, Peruzzi P, Reinhart B, Cohen JB, Chiocca EA, Glorioso JC. 2009. "Design and application of oncolytic HSV vectors for glioblastoma therapy" Expert Rev Neurother. 9:505-17. | Abstract
- Goins WF, Goss JR, Chancellor MB, de Groat WC, Glorioso JC, Yoshimura N. 2009. "Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain" Gene Ther. 16:558-69. | Abstract
- Miyazato M, Sugaya K, Goins WF, Wolfe D, Goss JR, Chancellor MB, de Groat WC, Glorioso JC, Yoshimura N. 2009. "Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord-injured rats" Gene Ther. in press | Abstract
- Uchida H, Shah WA, Ozuer A, Frampton AR Jr, Goins WF, Grandi P, Cohen JB, Glorioso JC. 2009. "Generation of herpesvirus entry mediator (HVEM)-restricted herpes simplex virus type 1 mutant viruses: resistance of HVEM-expressing cells and identification of mutations that rescue nectin-1 recognition" J Virol. 83:2951-61. | Abstract
- Srinivasan R, Wolfe D, Goss J, Watkins S, de Groat WC, Sculptoreanu A, Glorioso JC. 2008. "Protein kinase C epsilon contributes to basal and sensitizing responses of TRPV1 to capsaicin in rat dorsal root ganglion neurons" Eur J Neurosci. 28:1241-54. | Abstract
- Glorioso JC, Fink DJ. 2009. "Herpes vector-mediated gene transfer in the treatment of chronic pain" Mol Ther. 17:13-8. | Abstract
- Grant KG, Krisky DM, Ataai MM, Glorioso JC 3rd. 2009. "Engineering cell lines for production of replication defective HSV-1 gene therapy vectors" Biotechnol Bioeng. 102:1087-97. | Abstract
- Craft AM, Krisky DM, Wechuck JB, Lobenhofer EK, Jiang Y, Wolfe DP, Glorioso JC. 2008. "Herpes simplex virus-mediated expression of Pax3 and MyoD in embryoid bodies results in lineage-Related alterations in gene expression profiles" Stem Cells 26:3119-29. | Abstract
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