RNAi therapeutics
From DrugPedia: A Wikipedia for Drug discovery
[edit] RNAi therapeutics
RNA interference (RNAi) is an evolutionary conserved, gene silencing mechanism mediated through small non-coding RNA. It plays a significant role in the development of organism and also maintains the integrity of the genome by combating viruses and transposons. The RNAi pathway is complex phenomenon that is triggered by double stranded RNA (dsRNA). The enzyme Dicer process the dsRNA to generate 20-25 bp fragments and one of the two strand bind to the RISC (RNA-induced silencing complex) that subsequently bind to the mRNA in sequence specific manner to degrade or supress the mRNA. The short 20-25 bp fragments are known as small interfering RNA (siRNA) when they are produced from dsRNA and microRNA (miRNA) when they are produced endogenously as hairpin loop structure. The selective and robust effect of RNAi on gene expression makes it a valuable research tool in molecular biology laboratory to knock down specific genes. Thus it helps in the identification of the function of gene in particular cellular process. Exploitation of the pathway is also a promising tool in medicine to shut down a disease-causing gene.
RNAi and traditional pharmaceutical drugs To develop a highly specific and potent drug is a challenge. Most human disease is caused by abnormal production of proteins. Today traditional pharmaceutical drugs (small molecules and peptides) bind based on the shape of proteins, charge interactions and block the action of disease causing proteins. Developing a drug a time consuming process. Moreover, many molecules are non-druggable by the traditional drugs. The limitations associated with traditional drug can be overcome by using RNAi therapeutics.
Drug Discovery has two major concerns (1) Finding targets: (2) Destroying/suppressing targets: These properties can be achieved by exploiting RNAi technology.
(1) Finding targets: Identification of drug target is very easy and less time taken by this method. (2) Highly specific and potent to destroy targets: small dsRNA of 22nt long, siRNAs, of complementary sequence of target can be used to destroy the target gene. (3) Easy to synthesize and rapid lead optimization: Order of the nucleotides of siRNA can be changed to make the varieties of target specific. (4) Distribution and metabolism: These drugs are very similar from drug to drug, resulting in a common and often times, predictable, safety. (5) Nondruggable targets: sometimes we couldn’t design a drug for a particular protein due to lack of highly specific site within the protein. Such type of nondruggable target can be efficiently knockdown using RNAi mechanism. (6) Stability and specificity: Chemical modification can be used to increase the plasma stability and decrease its off target effect.
[edit] Current clinical trial
RSV-respiratory syncytial virus Alnylum Therapeutic developed ALN-RSV01 that target the nucleocapsid "N" gene of the RSV that is critical for the replication of the virus AMD- Age- related Macular Degeneration Sirna Therapeutic developed Sirna-027 that target VEGF responsible for developing blood vessel at macula of retina.
In the near future, the ongoing clinical trial with siRNA for different diseases may reveal the exciting potential of RNAi therapeutics as the next major class of drug molecules.
