RNAi has matured into a potentially revolutionary technique which silences gene expression in cells. Scientists can study the molecular effects of modulating expression at the level of individual genes. This degree of precision can now be accomplished without the time-consuming efforts previously dedicated to the construction of single gene knockouts or dominant negative cell lines.
Certain key cytokines orchestrate airway inflammation, which underlies airway hyperresponsiveness, while others regulate the production of immunoglobulin E (IgE) in allergic asthmatics. Knocking out these cytokines by systemic or local (aerosol) delivery to the respiratory tract would be of obvious benefit in treating the disease.
Sirna is specifically targeting key Th2 cytokines that play a critical role in inflammation and airway broncoconstriction. Previous clinical data has demonstrated a critical role for cytokines generated by Th2 lymphocytes in the pathogenesis of asthma. Sirna is currently developing the siRNAs formulated to provide a long duration of activity after local administration to the lungs.
Results of preclinical animal studies conducted in collaboration with the National Jewish Medical and Research Centre used chemically modified, systemically delivered short interfering RNAs (siRNAs). The results showed statistically significant reduction of airway hyperresponsiveness (66 per cent) in the RNAi treatment group.
"Short interfering RNAs in the treatment of asthma has demonstrated proof of feasibility in animal models that siRNAs may prove to be a very novel and effective therapy for treating asthma in humans," commented Dr Erwin Gelfand, chairman, department of pediatrics, National Jewish Medical and Research Centre.
"Patients will receive significant benefits from the application of an RNAi therapy to treat this very prevalent and chronic disease."
Despite extensive progress in the understanding of the etiology and treatment of asthma, the prevalence of asthma has been steadily increasing for the past 20 years. Although there are many pharmaceutical treatments that manage asthma symptoms, there are no drugs that effectively modulate the progression of the disease. The US market for asthma therapies in 2003 totalled $11 billion.
Asthma currently affects 15 million people in the US and is the leading cause of childhood hospital admissions as well as absenteeism from work. Approximately 5,000 deaths per year are attributed to the condition.
Sirna is amongst a handful of companies developing a new class of nucleic acid-based therapeutics involving RNA interference. RNAi is a mechanism used by cells to regulate the expression of genes and replication of viruses. The RNA interference mechanism uses short interfering RNA (siRNA) to induce the destruction of target RNA using naturally occurring cellular protein machinery.
Harnessing the natural phenomenon of RNAi holds potential for the development of a new class of drugs with specificity towards a wide range of diseases that result from undesirable protein production or viral replication.
Four leading companies in siRNA research for therapeutic applications are Alnylam Pharmaceuticals, Sirna Therapeutics, Acuity Pharmaceuticals and Atugen. Atugen was a spin-off of Sirna (1998) but is now an independent company competing with Sirna in this sector.
Benitec of Australia has joined this list of leading providers with its DNA directed RNAi (ddRNAi) therapeutics. Apart from this, Benitec also offers target validation services. Devgen NV, utilizing its proprietary RNAi technology, develops knockdown C. elegans for target validation. Deltagen Inc., based on mouse gene knockout and standardized phenotypic analysis, has developed DeltaBase, a searchable database for in vivo derived mammalian gene targets and function.