Targeted therapeutics company Arrowhead Research Corporation announced the publication of data demonstrating that high level target gene knockdown with low doses of cholesterol-siRNA is possible in non-human primates using the company’s Dynamic Polyconjugate (DPC) delivery system and a novel co-injection strategy. This new delivery approach dramatically increases the efficacy of cholesterol-siRNA and, together with the co-injection strategy, simplifies the manufacturing process to enable a commercially scalable delivery vehicle for RNAi therapeutics. The company is using this strategy and a next generation DPC polymer in ARC-520, its hepatitis B clinical candidate.
The publication describes an important advance in DPC technology. Specifically, the requirement for siRNA attachment to the DPC polymer is replaced by conjugating a cholesterol to the siRNA and co-injecting it with the DPC polymer. Uptake of the DPC in the target cells and subsequent unmasking of the polymer’s endosomolytic properties enables release of the cholesterol-siRNA from the endosome to the cell’s cytoplasm where it can elicit RNAi. This delivery strategy produces over 500-fold increase in efficiency in mice compared to injection of cholesterol-siRNA alone and is the first delivery system to demonstrate cholesterol-siRNA mediated gene knockdown in monkeys. Long duration silencing was observed after administration of a single dose with maximal protein reduction sustained until day 30. Further, unlike other siRNA delivery platforms, the co-injection method does not require complex formation of the siRNA to the delivery vehicle, which eliminates potentially complicated and costly manufacturing steps. This represents a seminal advance in the siRNA delivery field.
“The main drawback of cholesterol-conjugated siRNAs is that their delivery is highly inefficient, and extraordinarily high doses would be needed to achieve even minimal amounts of target gene silencing,” said Bruce Given, MD, Arrowhead’s COO and Head of R&D. “Our strategy and the DPC platform enable much higher levels of gene silencing at dramatically lower doses of cholesterol-siRNA. Moreover, the ability to simply co-inject the cholesterol-siRNA with the DPC polymer without having to attach them together simplifies manufacturing and has facilitated our use of next generation polymers. This co-injection strategy and a next generation polymer are being used in our HBV clinical candidate, ARC-520.”
Illustration: Arrowhead Research Corporation.
Arrowhead Research Corporation News Release (11/27/12)
Abstract (Nucleic Acid Therapy; 22(6), 380-390 (12/2012))