Biogenesis of MicroRNAs View image detail
RNAi in the Clinic
The speed with which RNAi therapeutics are progressing towards the clinic only six years after Tuschl and colleagues published on the first synthetic siRNAs is impressive. The number of RNAi-based clinical development programs continues to grow rapidly. While most of these programs utilize direct RNAi delivery applications, the first systemically delivered RNAi drug candidates are beginning to enter the clinic.
Confirming pre-clinical data, clinical experience has shown that siRNA-based drugs are safe and well tolerated over a wide range of dosages. In the largest safety study of its kind, Alnylam and their collaborators have treated nearly a hundred volunteers with an siRNA drug candidate for RSV infection and found it to be comparable to placebo controls in terms of safety and tolerability.
Trials in progress for the treatment of AMD further suggest clinical activity of RNAi therapeutics, and first definitive proof-of-concept of an RNAi drug candidate may well emerge in the near future from randomized, placebo-controlled, double-blind studies of RNAi therapeutics for RSV infection or hypercholesterolemia as well as in other indications. Recently, a double-blind, placebo-controlled clinical study of Alnylam’s RNAi therapeutic targeting RSV demonstrated statistically significant anti-viral efficacy; the so-called “GEMINI” study thus represents the first evidence for the ability of RNAi therapeutics to work in man.
Clearly, the prospect of RNAi therapeutics to address diseases of significant unmet medical need, but for which there are genetically well validated targets not druggable by the traditional approaches is quite exciting. RNAi drug candidates for the treatment of a number of previously intractable neurodegenerative diseases and cancers are expected to soon undergo human testing. Accelerated progress towards the clinical use of RNAi may further be due to public initiatives to harness RNAi for protecting the public from emerging viral threats such as Ebola and pandemic flu.
