RNAi Delivery
The key to success in RNAi therapeutics lies in delivering intact RNAi compounds to the target tissue and the interior of the target cells. To accomplish this, RXi is pursuing a comprehensive program that includes oral, systemic and local delivery approaches. These approaches take advantage of direct delivery of RNAi compounds and administration of RNAi compounds using an additional delivery vehicle.
| rxRNA™ Delivery Using Vehicles | Direct rxRNA™ Delivery |
| Oral delivery with GeRPs | Advanced rxRNA compounds |
| Systemic delivery | |
Oral Delivery with GeRPs:Many RNAi therapeutic products being developed today require recurring intravenous injections or other forms of administration that are not well-suited to clinical needs and are not patient friendly. To address the need for RNAi therapeutics with improved modes of administration, RXi is using a novel formulation technology – Glucan Encapsulated RNAi Particles, or simply GeRPs (Figure 1) – that may allow our rxRNA™ compounds to be incorporated into orally administered pills. In mouse studies (Aouadi, et al,
Nature, Vol. 458 (7242), pp. 1180-1184) it has been demonstrated that GeRPs deliver RNAi compounds directly to macrophages, key cells involved in the progression of various inflammatory diseases. Positive data from these pre-clinical studies leads us to believe that delivery of RNAi compounds to macrophages using GeRP technology may eventually be effective for the treatment of numerous
inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn’s disease and ulcerative colitis as well as other diseases such as atherosclerosis and diabetes.
Figure 1: The GeRP delivery system uses hollow, porous, micron-sized shells that can be filled with one or more types of RNAi compounds. Once ingested these shells are believed to be taken up by specialized M (Microfold) cells in the intestinal wall, and then transferred to immune cells residing in the underlying GALT (gut associated lymphatic tissue). Here, the GeRPs are then taken up by macrophages and other phagocytic cell types. Once in the macrophage, the RNAi compounds are presumed to be released from the GeRP shell into the cytoplasm where they would silence the specific target gene. As the macrophage migrates from the intestine/GALT to the other tissues in the body, the RNAi compound continues to silence the gene(s) causing disease.
Systemic Delivery:
RXi is developing a portfolio of advanced systemic delivery solutions for its RNAi technology platform. One of these solutions uses nanotransporters to aid in transport of RNAi compounds to various target tissues in the body, including the liver. The nanotransporters are chemically synthesized molecules that form small particles when mixed with RNAi compounds and help protect the RNAi compound in the body until it reaches the target tissue. Delivery of RNAi compounds to the liver might be critical for the treatment of many metabolic diseases [link to therapeutic areas page] and gene specific inhibition at low doses (1 mg/kg) in a mouse model using this technology has been achieved (Rana T et al (2007) ACS Chemical Biol).
Figure 2. A schematic diagram of a nanotransporter is shown on the left. On the right is data from a published experiment (Rana T et al (2007) ACS Chemical Biol) in which mice were administered 5 mg/kg of siRNA:nanotransporter intravenously daily for 3 days. The siRNA was stabilize and designed to target both Apo B-100 and Apo B-48 isoforms. The plasma was sampled at 24 hr post last dose.
Direct rxRNA™ Delivery:
RXi is developing a portfolio of advanced direct delivery solutions using its propriety rxRNA™ compounds. These rxRNA compounds are enhanced with features that will allow them to be administered without an additional delivery vehicle. Some of these features include proprietary composition and chemistry of the rxRNA™ compounds.
