The three basic requirements for an effective RNA interference-based therapy are 1) identification of key genetic defect[s] that provide pivotal survival advantage(s) to the overall cancer cell population; 2) construction of a potent and durable target-specific therapeutic agent; and 3) deployment of a tumor selective, non-immunogenic, RES-stealthed delivery vehicle. Stathmin 1 (STMN1), a critical regulator of tubulin polymerization/depolymerization, is overexpressed in 86% of our patients. We have constructed a unique bi-functional shRNA (bi-sh) with enhanced siRNA and miRNA activities. Bi-shSTMN1 is packaged as a decorated, reversibly masked, bilamellar invaginated lipoplex shorn of impurities through the use of a novel SuperClean DNA process. Our technical objective is to integrate this proprietary SuperClean DNA technology to extend the systemic therapeutic window of bi-shSTMN1. We will manufacture GMP grade SuperClean bi-shSTMN1 plasmid DNA and establish the systemic maximum tolerated dose of this lipoplex. By incorporating treatment controls of similarly-prepared parental GMP plasmid DNA, we can also identify toxicity that may be attributed to bi-shSTMN1 expression. These findings, together with the completion of our dose escalation Phase I protocol, will culminate in a phase I/II clinical study to determine safety and efficacy of systemic targeted delivery of BIV-bi-shSTMN1 with docetaxel in advanced melanoma.
NIH Spending Category: Biotechnology; Cancer; Genetics
Project Terms: Animals; base; Biodistribution; cancer cell; Clinical; Clinical Research; depolymerization; DNA; docetaxel; Dose; immunogenic; Masks; Maximum Tolerated Dose; melanoma; MicroRNAs; Mus; Mutation; novel; overexpression; Patients; Phase; Phase I Clinical Trials; plasmid DNA; Plasmids; polymerization; Population; pre-clinical; Process; RNA Interference; Safety; Small Business Innovation Research Grant; small hairpin RNA; Small Interfering RNA; stathmin; targeted delivery; Technology; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; trial comparing; Tubulin; tumor
