Attenuated Salmonella as a Delivery System for siRNA-Based Tumor Therapy
Posted Jun 15 2010 5:00pm
Description of Invention: The discovery that genes vectored by bacteria can be functionally transferred to mammalian cells has suggested the possible use of bacterial vectors as vehicles for gene therapy. Genetically modified, nonpathogenic bacteria have been used as potential antitumor agents, either to elicit direct tumoricidal effects or to deliver tumoricidal molecules. Bioengineered attenuated strains of Salmonella enterica serovar typhimurium (S. typhimurium) have been shown to accumulate preferentially greater than one-thousand fold in tumors than in normal tissues and to disperse homogeneously in tumor tissues. Preferential replication allows the bacteria to produce and deliver a variety of anticancer therapeutic agents at high concentrations directly within the tumor, while minimizing toxicity to normal tissues. These attenuated bacteria have been found to be safe in mice, pigs, and monkeys when administered intravenously, and certain live attenuated Salmonella strains have been shown to be well tolerated after oral administration in human clinical trials. The S. typhimurium phoP/phoQ operon is a typical bacterial two-component regulatory system composed of a membrane-associated sensor kinase (PhoQ) and a cytoplasmic transcriptional regulator. phoP/phoQ is required for virulence, and its deletion results in poor survival of this bacterium in macrophages and a marked attenuation in mice and humans. phoP/phoQ deletion strains have been employed as effective vaccine delivery vehicles. More recently, attenuated salmonellae have been used for targeted delivery of tumoricidal proteins.
This technology comprises live, attenuated Salmonella strains as a delivery system for small interfering double-stranded RNA (siRNA)-based tumor therapy. The inventors' data provide the first convincing evidence that Salmonella can be used for delivering plasmid-based siRNAs into tumors growing in vivo. Claimed in the related patent application are methods of inhibiting the growth or reducing the volume of solid cancer tumors using the si-RNA constructs directed against genes that promote tumor survival and cancer cell growth. The Stat3-siRNAs carried by an attenuated S. typhimurium described in the application exhibit tumor suppressive effects not only on the growth of the primary tumor but also on the development of metastases, suggesting that an appropriate attenuated S. typhimurium combined with the RNA interference (RNAi) approach may offer a clinically feasible method for cancer therapy.
Applications: Development of live attenuated bacterial cancer vaccines, cancer therapeutics and diagnostics.
Development Status: Vaccines have been prepared and preclinical studies have been performed.
Patent Status: HHS, Reference No. E-278-2007/0 CN, Application No. 200610017045.5 filed 26 Jul 2006 PCT, Application No. PCT/US2007/074272 filed 27 Jul 2007 , which published as WO 2008/091375 on 31 Jul 2008 US, Application No. 12/374,916 filed 23 Jan 2009
L Zhang et al. Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs. Cancer Res. 2007 Jun 15;67(12):5859-5864. [ PubMed abs ]
L Zhang et al. Effects of plasmid-based Stat3-specific short hairpin RNA and GRIM-19 on PC-3M tumor cell growth. Clin Cancer Res. 2008 Jan 15;14(2):559-568. [ PubMed abs ]
Licensing Status: Available for licensing.
Collaborative Research Opportunity: FDA-CBER Division of Bacterial, Parasitic, and Allergenic Products is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Salmonella-delivered anti-tumor therapies or Salmonella-vectored vaccines. Please contact Alice Welch at Alice.Welch@fda.hhs.gov for more information.
Portfolios: Cancer Cancer - Therapeutics Infectious Diseases Infectious Diseases - Therapeutics Infectious Diseases - Vaccines Infectious Diseases - Research Materials Gene Based Therapies Gene Based Therapies - Therapeutics In-vivo Data
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