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Jun 1, 2009 (Vol. 29, No. 11)

Delivery Approaches for RNAi-Based Drugs

Getting siRNA into the Right Place in the Cell Might Not Be a Problem for Much Longer

  • Nonliposomal Methods

    The use of aptamer-siRNAs will be covered by John Rossi, Ph.D., professor and chair, molecular biology, Beckman Research Institute. The power of the aptamer has increased by combining it with siRNAs to produce aptamers that are capable of selectively binding to human immunodeficiency virus type 1 (HIV-1) envelope protein, and ultimately blocking HIV-1 replication in cell culture.

    The HIV-1 envelope was selected as a target because it is expressed on the surface of HIV-1-infected T cells and serves as a receptor for viral entry. Although data on these aptamers has been previously published, Dr. Rossi will present new data on how these aptamers have been shown to inhibit HIV-1 replication in several types of cell culture, including primary T cells.

    He will also present an extension of the work in humanized mouse models for human stem cell engraftment. When a mouse model is treated with human stem cells, “the cells completely differentiate into all the lineages that HIV-1 infects in these mice, and in mice that have been treated with the aptamer we see complete suppression of HIV-1 replication, as compared to untreated controls, where replication is rampant,” says Dr. Rossi.

    “We think this is an exciting approach for treatment of HIV-1 infection because it allows us to keep pace with the virus, which mutates pretty rapidly against siRNA. We can keep changing the aptamer and/or siRNA as the HIV-1 targets change.”

    Johannes Fruehauf, M.D., Ph.D., vp of R&D at Cequent Pharmaceuticals, will talk about the company’s Transkingdom RNAi technology. Cequent focuses on the development of RNA-based therapeutics to treat human gastrointestinal disease. The company uses genetically engineered Escherichia coli cells to express, and then to deliver, therapeutic short hairpin RNA (shRNA).

    This platform has been used to develop Cequent’s first clinical candidate therapeutic RNAi-based drug to treat Familial Adenomatous Polyposis (FAP). Patients with FAP have inherited a nonfunctional copy of the Adenomatous Polyposis C  gene, which normally regulates expression levels of a key oncogene, beta-catenin, in intestinal epithelia.

    The mutated form of the gene causes uncontrolled levels of beta-catenin, which leads to formation of cancerous polyps in the colon. The idea behind this new clinical candidate is to treat FAP patients with a therapeutic shRNA that can effectively keep the levels of beta-catenin at bay, and thus eliminate the possibility of polyp formation in those patients. Cenquent expects to begin clinical trials in the fall.

    Development of RNAi-based therapeutics is relatively new to the pharmaceutical industry. Yet, in a short period of time, nearly all of the obstacles to the development of such drugs have been overcome. The remaining challenge is siRNA delivery. But with each advance, including the ones highlighted in this article, the pharmaceutical industry and academics alike will come closer to delivering RNAi-based drugs safely and on target.  

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