The Human Genome Project has identified 22,300 genes as potential targets, which can be, classified as addressable by protein therapeutics (~ 10,000 genes), disease modifying genes (~ 4500), additional targets for protein therapeutics (~1800 genes), targets for antisense and siRNA therapies (~2100genes), targets for small molecular drugs (~600 genes) and druggable genes (~3000 genes). On basis commercial viability of descending order of molecular targets fall into enzymes, GPCR, carrier, membrane receptors, ion channels, nuclear hormone receptors and miscellaneous.
The secrets of nature are holding a treasure of information, which on unfolding can lead to miracles in medicine. The post human genomic era has potential to revolutionize the therapeutics in unimaginable direction. Presently the diseases are haunting the mankind in various forms of severe morbidity and mortality. Diseases like diabetes mellitus, obesity, and hypertension are on raise both in developed and developing societies. The depression and bunch of unheard stress related psychosomatic diseases are urban specialties. The mundane infectious diseases are attacking the poor underprivileged as their safe havens. The AIDS tuberculosis, hepatitis, birds flu poses a threat of global epidemics. The development of resistance to the antibiotics has made many potential antibacterial a redundant.
The era conventional chemotherapy seems to have come to its dead end. The advent of gene therapy as a solace to control and contain morbidity and mortality has been rekindled after initial failures. The global initiatives from entrepreneurs and researchers have redefined the funding of research initiatives leading to a new model of drug discovery. Now the drug discovery companies are focused and practice research in a professional manner leading to reduction on investment with very high rates of success. The drug discovery companies are run by scientists themselves and can decide on the course of discovery path given them the much-required academic freedom.
The drug discovery has evolved over several decades of untiring efforts and zeal by academicians and scientists worldwide. The advances in basic sciences and technologies are the real catalysts of this progress. The multidisciplinary approach has proved to be the most successful leading to the understanding the pathological intricate details not only at the cellular level but also to the molecular levels. The understanding of the intricate details of happenings at molecular level was an offshoot of human genome global initiatives. The Human Genome Project has evolved due to the timely inputs from information technology, molecular biology, and biophysics. The combinatorial chemistry and high through-put screening are the technologies, which are expediting the drug discovery.
RNAi is the hottest technology in biotechnology front. It is set to revolutionize drug target discovery by evolving genomics from inferring correlation to determining causation. It even serves as a broad-based platform for developing targeted therapeutics against a wide range of diseases. It has the potential to widen the bottleneck of putative drug targets awaiting validation by rapidly and cost-effectively determining function.
Among all the evolving technologies of post genomic era, siRNA is emerging as the most promising technologies having potential to change the face of therapeutics. This new mechanism is now commonly referred to as RNA silencing. It is a general process in which dsRNA triggers sequence-specific repression of gene expression. The dsRNA is recognized by cellular machinery and assembled into ribonucleoprotein complexes that mediate the expression in a sequence-specific manner, according to principles of Watson-Crick complementarities.
SUMMARY OF GENE SILENCING IN AGE RELATED MACULAR DISEASES
In age related macular disease the pathological consequences happen through the up regulation of vascular endothelial growth factor (VEGF) up regulation. The siRNA acts on mRNA to block the VEGF production in cancerous cells and thus containing the cancer. The protein expression is a fundamental process, which holds the key for pathogenesis of many diseases like cancer, viral infectious diseases like hepatitis C, HIV, hepatitis B, influenza, severe acute respiratory syndrome (SARS) virus, polio virus, respiratory synctial virus disease, CNS disease and cardiovascular diseases.
The value of the drug discovery market based on RNAi can be assessed at $650 million in the year 2005, increasing to $1 billion in the year 2010 and $1.5 billion in 2015. There are nearly 122 companies involved in developing RNAi technologies. Approximately 16 of these are developing RNAi-based therapeutics Even if a few products get into the market by the year 2010, this market will expand to $3.5 billion based on revenues from sales of RNAi- based drugs and increase further to $5.9 billion in 2015.
Although currently no drug based on siRNA available in the market, its other applications like in research, diagnostics and other activities are on the raise and has done a business of ~ 60 million US $ business. The trends are such that, there will be si RNA based products likely to enter market by 2006. The projections depict the combined sale of therapeutics and R&D applications based on siRNA.
MARKET FOR DRUGS BASED ON SIRNA: FORECAST
Although a variety of methods can be used for the study of gene function, many of these, such as gene knockouts, transgenic animal models, and antisense RNA, are time-consuming, costly, and not amenable to high-throughput studies. siRNA-mediated RNAi presents many advantages. It is faster and less laborious than creating knockouts or transgenic animals. In addition, design of potent siRNAs is easier than design of effective antisense oligonucleotides. Studies have found that the biological activity of siRNA is approximately 100-fold higher than antisense oligonucleotides, meaning that siRNAs can be effective at much lower concentrations. The robustness of siRNA-mediated RNAi has resulted in its widespread use in high-throughput drug discovery research.
Application of silencing the gene function to regulate specific protein synthesis has direct bearing in many disease conditions. The cancer, viral infections often mediate their prognosis by protein synthesis. The silencing the gene function has resulted in therapeutics as novel method of disease intervention. As the process is on post-transcriptional, the toxicities can be estimated to be limited and less severe than the indiscriminate chemotherapy.
The Intervention of Protein Synthesis can also be possible with antisense approaches using oligonucleotides, aptamers, ribozymes, peptide nucleic acid and locked nucleic acid along with RNAi .In summary Si RNA has emerged as successful technologies due to its attributes. It is a post-transcriptional gene silencing, double-stranded RNAs are introduced into the cell, complementary to mRNA for a gene, can be directly introduced in a wet lab, or produced by the cell itself.
(Article is based on a talk delivered at IBC conference on drug discovery held in Mumbai recently.) (The author is with Pharmacy Group, Birla Institute of Technology and Science, Pilani, Rajasthan, India.)