Inappropriate gene activity is being linked to a growing number of diseases. The ability to modulate or silence such activity via RNA interference (RNAi) technologies could revolutionize the way we treat disease. RNAi, as a new class of drugs, has already been convincingly demonstrated in a number of preclinical models of diabetes, hepatitis, oncology, influenza, macular degeneration, Parkinson and Huntington diseases, and others.
RNAi therapeutics have enormous potential. Because they inhibit gene expression at the level of translation, they offer a unique opportunity to rapidly identify and potently inhibit disease targets. The total market for RNAi therapeutics could reach $580 million by 2012, according to Market Research. CHI’s recent “From Tools to Therapies” meeting highlighted challenges facing this young field, exciting new applications, delivery, and cutting-edge platforms.
The best RNAi product in the world is useless if it cannot be delivered effectively to the target. “Delivery of RNAi therapeutics is one of the biggest challenges the industry faces,” reported Ian MacLachlan, Ph.D., CSO of Tekmira Pharmaceuticals. “Nucleic acids are comparatively large molecules that also are unstable in the blood. Additionally, they cannot readily cross membranes into target cells. To reach the maximum therapeutic potential of RNAi-based drugs, effective delivery is crucial.”
While the mechanism is called RNAi, the therapeutic agents are the so-called short interfering RNAs (siRNA) that consist of ~21 nucleotides of double-stranded RNA. Dr. MacLachlan said that nanoparticles coated with lipids encasing the payload siRNA represent an emerging new approach for delivery. “In the early days, researchers were using naked siRNA or chemically modified versions. Although initially there were some good in vivo results, further studies were less encouraging. We found, however, specially coated nanoparticles can potentiate delivery by 1,000-fold.”
Tekmira’s siRNA delivery technology platform is called SNALP for stable nucleic acid-lipid particles. SNALP are specialized lipid nanoparticles that encapsulate and systemically deliver a variety of nucleic acid molecules such as siRNA.
“Our preclinical studies have shown them to be effective in delivering the drug to target organs and into cells where the nucleic acid-based drug can carry out its desired effect while minimizing systemic toxicity,” Dr. MacLachlan reported. “Tekmira and its partners will have five product candidates in clinical trials by the end of 2010.”
One application targets hypercholesterolemia. The technology, called ApoB SNALP, targets ApoB, a protein that is essential to the assembly and secretion of very low density lipoprotein, a precursor to low density lipoprotein (LDL), both of which are required for the transport and metabolism of cholesterol.
In animal studies, the ApoB SNALP are delivered with high efficiency into liver hepatocytes, the cells that produce ApoB. The payload siRNA acts to knock down the precursor mRNA coding for ApoB protein resulting in significant reductions in LDL.
Although the nanoparticle technology is currently used for systemic application, according to Dr. MacLachlan the field is moving toward a targeted modality. “A variety of research is under way to see how RNAi can be delivered to specific target cells. That’s the race for the future.”