Small interfering RNAs (siRNAs) are double-stranded RNA molecules that are able to silence a single gene in a sequence-specific manner by specific degradation of the target mRNA. Nastech is utilizing siRNAs in the laboratory as a research tool and is also actively pursuing their potential as human therapeutics.

RNAi as a Research Tool

RNA interference (RNAi) is an important tool that Nastech is using to analyze tight junction function and to determine the importance of individual tight junction proteins in regulating paracellular transport.  These types of studies help to identify which tight junction proteins are the most appropriate targets by which to modulate tight junction function.

We have developed siRNAs against various tight junction proteins and determined their effects on tight junction function. For example, we have determined whether siRNA inhibition of specific tight junction proteins affects transepithelial electrical resistance and increases tight junction permeability. These types of studies help to identify which tight junction components are the most appropriate targets to modulate in order to improve the passage of drugs through tissue barriers. The high specificity of individual siRNAs allows us to further characterize the differences in tight junctions that exist among distinct tissue types.

siRNAs as Human Therapeutics

RNAi technology shows great promise for the development of a new class of therapeutics. For example, using a specific siRNA as a drug to inhibit the expression of certain cytokines found in blood cells that play an important role in pathological inflammation may be an effective treatment for rheumatoid arthritis. Other potential targets include:
 

• Proteins that signal cells to become cancerous
• Beta-amyloid, a prime suspect in Alzheimer's disease
• Viral proteins that cause AIDS and hepatitis

Most small molecule drugs are able to reach their targets because they can passively diffuse into and out of cells through the cell membrane. Larger and more complex molecules (peptides, proteins, and oligonucleotides) by themselves have greater restriction in passing through tissue barriers by either the paracellular route or by traversing the cell’s plasma membrane. Nastech has developed advanced formulations that significantly improve paracellular delivery. The development of novel carrier molecules is a promising approach to intracellular delivery of siRNA drugs.

Challenges for delivering siRNAs as drugs are similar to those for other large molecule drugs:

• Delivery through tight junction tissue barriers
• Maintaining the stability of the molecule
• Intracellular delivery—getting siRNAs across cell membranes, into cells in sufficient quantities to be effective

Nastech's chemistry and formulation science expertise allow us to create the conditions under which siRNA will remain stable and active.

Our experience and intellectual property around tight junctions and permeation enhancement will enable us to place siRNAs inside target tissues and cells.

Nastech is establishing a very competitive therapeutic development program through the combination of our:

• Tight junction modulation technology
• New methods for improved cellular uptake of siRNA molecules