Joseph C. Glorioso, III, PhD
433 Bridgeside Point II
450 Technology Dr.
Pittsburgh, PA 15219
Dr. Glorioso has established a 35-year history of research related to the basic biology and genetics of herpes simplex virus. His contributions to the field include defining antiviral immune responses to infection, the genetics of viral pathogenesis and latency, and mechanisms of viral infection. Furthermore, he has been a pioneer in the design and application of HSV gene vectors for the treatment of nervous system diseases such as peripheral neuropathies, chronic pain and brain tumors. He continues to be a worldwide leader in the HSV gene vector field through the creation of innovative gene vectors and the development of manufacturing methods for Phase I and Phase II human clinical trials for pain gene therapy. His enkephalin vector showed considerable promise in a Phase I human trial to treat cancer pain and phase II testing is underway. These trials were sponsored by Diamyd Medical AB in Stockholm. Dr. Glorioso is a Diamyd stockholder.
Dr. Glorioso’s most recent research has focused on (i) the design and application of HSV gene vectors for exploring the molecular events that occur in sensory afferents that are involved in the transition from acute to chronic pain, (ii) the development of retargeted oncolytic HSV vectors for specific infection and replication in human glioblastomas and applications to treatment of xenograft models of human brain human brain tumors, (iii) the creation of novel HSV vectors that cross the blood brain barrier by transcytosis followed targeted infection and gene expression in spiny neurons of the striatum; these vectors are being applied to treatment of animal models of Huntington’s disease and (iv) the use of HSV gene vectors for the creation of induced pluripotent stem (iPS) cells and the identification of transcriptional regulatory and signaling processes that participate in cellular reprogramming.
Over the years, his laboratory has studied the structure/function domains of the HSV envelope glycoproteins that play a role in cognate receptor recognition and activation of the fusion/entry mechanism. HSV relies on 4 essential glycoproteins (gD, gB, gH, gL) to gain entry into cells. gD binding to its natural receptors, HVEM or nectin-1, results in signaling events required for activation of the gB-gH/gL membrane fusion apparatus. Virus envelope fusion with cell membranes releases the virus capsid into the cytoplasm whereupon it is trafficked to the nucleus, viral DNA is released into the nucleoplasm and the replication cycle is initiated. These studies have enabled the genetic manipulation of these attachment/entry function to create viruses with novel tropisms for neurons and tumor cells. For example, we have engineered HSV vectors for infection of stem cell markers, tumor markers and neurotrophic factor receptors. The safety of these vectors have been further enhanced by microRNA control of essential gene expression in normal brain.
Retargeted, miR controlled vectors are also being exploited for selected gene expression in neurons of the peripheral and central nervous system. Of particular interest are a new generation of vectors that express neuron silencing by drug activated ion channels. The application of neuron silencing methods hold great promise for mapping neurons involved in cognitive processes and chronic pain signaling.
|Fang Han, Tsinghua Univ. Visiting Scholar ||Mindgi Zhang, Senior Research Specialist|