RNA

RNA Drug Signals Delivered Systemically.

RNA interference (RNAi) is part of a larger set of cellular responses to RNA, collectively called RNA silencing, which play an important role in the regulation of cell growth and differentiation for virtually every life form above the level of bacteria. RNAi works by destroying the molecular messengers that carry information coded in genes to the cell’s protein factories. These molecules, called messenger RNAs (mRNAs), perform a critical function without which a gene is essentially inactive.

Nativis is developing a-PCSK9s, a drug signal therapeutic, for the treatment of high cholesterol. Hypercholesterolemia is a major risk factor for cardiovascular disease, the leading cause of death in the United States. a-PCSK9s is an antisense RNA drug signal that targets PCSK9 (proprotein convertase subtilisin/kexin type 9) mRNA for degradation. PCSK9 is a protein involved in the downregulation of the cell surface receptor that captures LDL particles and internalizes them within the cell. Inhibition of PCSK9 expression increases the number of LDL receptors available to remove LDLc (“bad cholesterol”) from the bloodstream. Elevated PCSK9 expression has been associated with high levels of plasma LDLc and individuals displaying loss of function mutations in PCSK9 exhibit reduced LDLc, as well as reduced risk for coronary heart disease.

In preclinical studies using a high fat, diet-induced obesity mouse model, Nativis has preliminary results that suggest systemic delivery of a-PCSK9s:

• PCSK9 mRNA reduction up to 95% in 24 hours
• 36% reduction of LDLc in 24 hours (HDLc, the “good” cholesterol, remained unchanged)

We are simultaneously developing multiple delivery methods for this product as well as for Digitax™, including the addition of an aqueous composition delivery system to the already established electronic delivery via our proprietary MIDS™ and Voyager™ technologies. (Apart from the therapeutic advantages of drug signal technology, systemic deliverability of PCSK9 eliminates what has long been a major obstacle to the commercialization of RNA products in general.)