Protease Activation of Newcastle Disease Virus for Oncolytic viral therapy

新城疫病毒蛋白酶激活用于溶瘤病毒治疗

• 批准号: 7497045
• 负责人: Elankumaran Subbiah
• 金额: $ 27.21万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497045
• 关键词: Amino Acids; Antigens; Antiviral Agents; Attention; Avulavirus; Birds; Cell surface; Cells; Cessation of life; Chickens; Chimeric Proteins; Cleaved cell; Clinical Trials; Complementary DNA; Conjunctivitis; Development; Disease; Drug resistance; Elastases; Endopeptidases; Engineering; Enzymes; Eukaryotic Cell; Evaluation; Family; Future; Genetic Engineering; Glycoproteins; Goals; Growth; Heart Diseases; Histocompatibility Testing; Human; Immune; Immunity; Leukocyte Elastase; Ligands; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Methods; Modeling; Mus; Neoplasm Metastasis; Neprilysin; Newcastle disease virus; Normal Cell; Oncolytic; Oncolytic viruses; PC6 extract; Pancreatic Elastase; Paramyxovirus; Patients; Peptide Hydrolases; Plasmids; Pliability; Protein Overexpression; Proteins; Proteolysis; Qualifying; RNA Viruses; Recombinants; Research; Role; Safety; Sendai virus; Site; Subtilisin; Subtilisins; Surface; System; Therapeutic; Therapeutic Index; Tissues; To specify; Tropism; Trypsin; Tumor Cell Invasion; Tumor Cell Line; Tumor Tissue; United States; Upper arm; Vesicular stomatitis Indiana virus; Viral; Viral Fusion-GP; Virulent; Virus; Zinc; antitumor agent; base; cancer cell; cancer therapy; cell type; chemotherapy; design; experience; improved; in vivo; killings; mutant; neoplastic cell; novel; oncolysis; positional cloning; receptor; recombinant virus; therapeutic transgene; tissue tropism; tool; tumor; tumor growth; virus host interaction

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.

描述（由申请人提供）：溶瘤病毒治疗近年来引起了人们的关注，部分原因是由于对病毒-宿主相互作用的理解取得了进展，而且由于许多原因，包括对药物的耐药性的发展，目前可用的化疗并不完全令人满意。目前流行的主要溶瘤治疗策略很大程度上依赖于某些病毒的天然肿瘤选择性，如新城疫病毒（NDV）和水疱性口炎病毒（VSV）。但是，由于受体在许多类型的细胞上的可用性，靶向肿瘤治疗直到现在才成为可能。此外，天然存在的溶瘤菌株的效力有限。随着从克隆的cDNA中完全恢复感染性病毒的反向遗传学技术的出现，通过表达治疗性转基因重新靶向溶瘤RNA病毒并增强其疗效，以及对病毒包膜进行伪分型以逃避宿主抗病毒免疫现已成为可能。靶向、武装和隐身溶瘤RNA病毒将增强未来的癌症治疗。基质金属蛋白酶（MMPs）和其他肿瘤特异性蛋白酶在许多恶性细胞中高水平表达，使其传播和转移成为可能。NDV是一种非节段副粘病毒，在体内通过组织特异性胰蛋白酶样酶裂解激活病毒融合糖蛋白在靶组织中传播。NDV是一种天然的肿瘤选择性和固有的溶瘤病毒。我们建议将该病毒融合糖蛋白的色氨酸切割位点改变为对MMPs或人中性粒细胞弹性酶敏感的位点。我们假设重组病毒将不再被胰蛋白酶激活，而是需要特定的蛋白酶，并在表达这些蛋白酶的人类肿瘤细胞中有效地传播。此外，我们还预计病毒会在分泌特定蛋白酶的异种移植肿瘤中广泛传播，而不会传播到正常细胞，从而抑制肿瘤生长。我们的研究结果将证明重组蛋白酶激活NDV突变体选择性靶向和杀死人类肿瘤细胞的潜力。此外，根据患者分泌的蛋白酶类型“个性化”溶瘤性NDV的能力为该方法提供了最大的灵活性。此外，该方法还可以与现有的配体定向靶向方法相结合，进行特异性靶向和溶瘤。在美国，癌症是导致所有死亡的主要原因之一，仅次于心脏病。我们在此建议对新城疫病毒（一种固有的溶瘤病毒）进行基因修饰，使其靶向分泌特定蛋白酶的人类肿瘤细胞。我们的方法将产生一种蛋白酶靶向溶瘤病毒，可以根据患者的个体化。

项目成果

Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors.

• DOI: 10.2147/ott.s132964
• 发表时间: 2017
• 期刊: OncoTargets and therapy
• 影响因子: 4
• 作者: Rossmeisl JH;Hall-Manning K;Robertson JL;King JN;Davalos RV;Debinski W;Elankumaran S
• 通讯作者: Elankumaran S