Protease Activation of Newcastle Disease Virus for Oncolytic viral therapy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Oncolytic virus therapy is attracting attention in recent years in part due to the progress in understanding virus- host interactions and because currently available chemotherapy is not completely satisfactory for many reasons, including the development of resistance to drugs. The major oncolytic therapeutic strategies in vogue largely rely upon the natural tumor selectivity of certain viruses, such as Newcastle disease virus (NDV), and Vesicular stomatitis virus (VSV). But, due to the availability of receptors on many types of cells, targeted tumor therapy was not possible until now. Besides, naturally occurring oncolytic strains are limited in their efficacy. With the advent of reverse genetics to recover infectious virus completely from cloned cDNA, retargeting the oncolytic RNA viruses and enhancing their efficacy through expression of therapeutic transgenes, and pseudo-typing the viral envelope to evade host antiviral immunity is now possible. Targeted, armed and stealth oncolytic RNA viruses will enhance cancer therapeutics in future. Matrix metalloproteinases (MMPs) and other tumor specific proteases are expressed at high levels in many malignant cells to enable their dissemination and metastasis. NDV, a non-segmented paramyxovirus, spreads in target tissues in vivo via cleavage activation of the viral fusion glycoprotein by tissue-specific trypsin-like enzymes. NDV is a naturally tumor-selective and inherently oncolytic virus. We propose here, to change the tryptic cleavage site of the fusion glycoprotein of this virus to a site susceptible to MMPs, or human neutrophil elastase. We hypothesize that the resultant recombinant virus will no longer be activated by trypsin but will require specific proteases and spread efficiently in human tumor cells that express these proteases. Furthermore, we also expect the virus to spread extensively in specific protease secreting xenotransplanted tumors without disseminating to normal cells, leading to the inhibition of tumor growth. Our results will demonstrate the potential of selective targeting and killing of human tumor cells by recombinant protease activation mutants of NDV. Further, the capability to "individualize" the oncolytic NDV according to the type of protease secreted in the patient offers the greatest flexibility to this approach. In addition, this method can also be combined with currently available ligand-directed targeting approaches for specific targeting and oncolysis. Cancer is one of the leading causes of all deaths in the United States, exceeded only by heart diseases. We propose here to genetically modify Newcastle disease virus, an inherently oncolytic virus, in such a way that it targets specific protease secreting human tumor cells. Our approach will yield a protease-targeted oncolytic virus that can be individualized according to the patient.