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 developing novel and advanced delivery technologies that may enable the delivery of our rxRNA™ compounds to treat a variety of acute and chronic diseases using local, systemic and oral administration. Our suite of delivery technologies is comprised of delivery vehicles, which can be combined with various rxRNA compounds, as well as sd-rxRNA™ (or "self-delivering" RNA) compounds, which have the unique property of entering cells and tissues to effect silencing without the need for any additional delivery vehicle. This suite of delivery technologies has broad potential applications for multiple therapeutic areas targeting both local and systemic applications.

 

 

Local Delivery 

With local delivery, a drug is delivered directly to the tissue of interest.  sd-rxRNA molecules have unique properties which improve tissue and cell uptake. Delivery of sd-rxRNA by a local route may avoid some of the hurdles associated with systemic delivery, such as circulation clearance and crossing the endothelial barrier from the blood stream. However, this approach can only be applied to a limited number of organs or tissues. Target tissues that are potentially accessible using rxRNA compounds in the context of a local delivery approach include lung, eye, compromised skin, CNS, mucosal tissues, sites of inflammation, and tumors (direct administration).


Systemic Delivery
Systemic delivery occurs when a drug accesses the tissue of interest through the circulatory system. In some cases, such as in targeting a treatment to the liver, the optimal route of delivery may be systemic. RXi is developing a portfolio of advanced systemic delivery solutions utilizing its RNAi therapeutic platform. One novel approach involves the use of sd-rxRNA compounds. The self-delivering technology introduces properties required for in vivo efficacy such as cell and tissue penetration and improved blood clearance and distribution properties. In addition, RXi has developed novel nanotransporter formulations to aid in transport of RNAi compounds to various target tissues in the body, including the liver. These 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 diseases and using rxRNA in conjunction with such delivery vehicles has enabled us to demonstrate gene specific inhibition at low doses in a mouse model after intravenous, systemic delivery. Target tissues that are potentially accessible using rxRNA compounds by systemic delivery include liver, lung, adipocytes, cardiomyocytes, bone marrow, sites of inflammation, tumors, vascular endothelium, and kidney.    
 

 
Local or Systemic Delivery with sd-rxRNA

sd-rxRNA is a novel single RNAi compound that is modified to enable delivery to target cells and organs and efficient cellular uptake without the use of an additional delivery vehicle.  The potential drug-like properties that RXi is designing into its sd-rxRNAs for both local and systemic therapeutic applications include:

  1. Serum stability
  2. Reduced renal clearance
  3. Target tissue uptake and penetration
  4. Reduced immune response activation
  5. Spontaneous cellular uptake
  6. Productive RISC loading

 

Oral Delivery
Many RNAi therapeutic products being developed today require recurring intravenous injections or other forms of administration that are not patient friendly.  To address the need for RNAi therapeutics with improved modes of administration, RXi is testing a novel formulation technology – Glucan Encapsulated RNAi Particles, or simply GeRPs – that may allow our rxRNA compounds to be incorporated into orally administered pills.  Early data to date suggest that the GeRP delivery system appears to be more potent than previous methods used for systemic delivery of RNAi therapeutics by intravenous injection.  Additional studies will need to be conducted to clearly establish the flexibility of the GeRP system and to determine whether they can either be used to administer a single RNAi compound, multiple RNAi compounds, or could potentially allow co-delivery of RNAi, DNA, protein and small molecule combinations.