Arrowhead Research scientists claim RNA delivery bull’s eye

In theory small interfering RNA (siRNA) molecules can block gene expression by interacting with mRNA before it is translated into protein and therefore have application in the treatment of various genetic disorders.

The problem is that delivering the fragile siRNA molecules is a complex challenge that has already seen a number of pharmaceutical companies opt to abandon their development efforts, most notably Roche which sold its siRNA assets to Arrowhead in 2010.

However, several developers are still convinced of siRNA’s potential with firm’s like Alnylam​, Silence Therapeutics and Tekmira all working to address the delivery problem.

Delivery bull's eye​

The Arrowhead team’s approach to the problem – which is published here​ – was to improve the efficacy of cholesterol conjugated siRNA – which must be injected three times a day in mice to produce a measurable effect – by adding an vesicle bursting - or endosomolytic polymer – to the injection.

And the plan seems to have worked. According to the results of the study the combined injection was 500 times more effective than chol-siRNA alone and brought about a 90 per cent reduction in target gene expression in mice and – for the first time – in non-human primates.

The authors wrote that: “This improved efficacy is achieved by the co-injection of a hepatocyte-targeted and reversibly masked endosomolytic polymer.​

“Importantly, we provide evidence that this increase in efficacy is not dependent on interactions between the chol-siRNA with the polymer prior to injection or in the bloodstream. The simplicity of the formulation and efficacy of this mode of siRNA delivery should prove beneficial in the use of siRNA as a therapeutic​.”