RNA therapeutics are new, innovative high-impact medicines. The combined efforts of pioneering biotechnology companies, pharmaceutical and academic institutions have helped these treatments, which act on ribonucleic acids in the cell, to evolve and come of age.
For those unfamiliar, these medicines are designed to target RNA and can ultimately affect many cellular components. They can provide numerous distinct advantages when compared to conventional methods of targeting proteins with small-molecule chemical compounds, or large-molecule protein drugs like antibodies. By targeting RNA, scientists now have the opportunity to develop drugs for a plethora of diseases which can’t be treated today with conventional methods. Moreover, RNA therapies have the potential to synergize with existing therapies and can address severe unmet medical needs such as cancer, cardiovascular disorders and autoimmune diseases.
The world of RNA therapeutics consists of several different kinds of technologies, including antisense therapies, RNA interference (RNAi) therapeutics, nucleic acid or peptide aptamers and microRNA therapeutics. RNA is one of three major macromolecules in a cell and is made up of a long chain of nucleotides. It is a single-stranded molecule that can adopt very complex three-dimensional structures and can affect many cellular functions. RNA is a critical molecule involved in many cell activities. RNA may be the first molecule that allowed life to pass genetic information from one generation to the next. There is also evidence that RNA may have been the primordial source of life.
However, a key question has always been: can targeting RNA translate into first-in-class, powerful therapeutic drugs? For more than two decades, academic institutions, biotech and large pharmaceutical companies have been investigating the answer to this question.
Deregulation of protein expression may be a primary cause of chronic illnesses such as cancer, cardiovascular and autoimmune diseases. Therefore, therapies that may directly inhibit the overexpression of the disease-causing proteins may address these chronic illnesses. RNA therapies aim to prevent the translation of these proteins and ultimately block their production.
RNA therapeutics represent an exciting and potentially transformative approach to developing new treatment regimens. Part of the appeal with RNA therapies is that while they can be effective on their own, they can work in combination with existing treatments. That means RNA therapeutics do not have to necessarily displace existing therapies to provide a benefit to patients.
In the world of drug discovery and development, full of small molecules and larger protein drugs, typically there is one established target and numerous drug candidates competing to hit the target with the best combination of safety and effectiveness. However, there is still a very large space of unmet medical need. Oral drugs cover a significant portion of drug targets, followed by non-oral drugs, such as monoclonal antibodies. But collectively, these types of therapies can address only a small portion of all potential targets. Targeting RNA has created the ability to venture into a whole new space, essentially covering the entire genome, with new mechanisms of action that can be combined with current therapies.
There are multiple ways for these nucleic acid therapies to affect a particular target. With antisense therapies, such as those pioneered by Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: ISIS), the goal is to synthesize a strand of nucleic acid that will bind to the messenger RNA (mRNA) produced by the gene that is causative of a particular disease and inactivate it by effectively turning that gene “off.” Antisense therapies target the proteins involved in disease processes through the RNA that is involved in building these proteins. The Isis discovery platform develops specific therapies that bind to mRNA and inhibit the production of disease-causing proteins. Currently, there are over 25 different drugs in development that are based on the antisense mechanism. The most advanced is mipomersen (Kynamro), a novel, first-in-class, apo-B synthesis inhibitor for the reduction of LDL cholesterol. This drug acts by decreasing the production of apolipoprotein-B, which provides the structural core for atherogenic lipids, including LDL-C, which carry cholesterol through the bloodstream. Clinical trials have shown mipomersen reduces LDL-C and other key atherogenic lipids linked to cardiovascular disease by preventing their formation. Earlier this month, the FDA approved the treatment for patients in the United States.
The development of RNA interference (RNAi) therapeutics has been led by Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY), which invested along with Isis in 2007 to form the company that I lead, Regulus Therapeutics. RNAi therapeutics also target mRNA molecules but through a different mechanism. This occurs in the cytoplasm of the cell with the aid of the RNA Induced Silencing Complex (RISC). In terms of target space, both antisense and RNAi can target mRNAs, although their mechanisms are fundamentally different. RNAi utilizes double stranded RNA, whose role is to find the target messenger RNA and promote its degradation. Alnylam has shown proof-of-concept in clinical trials of several RNAi drug candidates, including one for a rare disease called TTR amyloidosis.
Nucleic Acid or Peptide Aptamers
Another therapeutic approach to treating human disease is nucleic acid or peptide aptamers which bind to a specific target molecule. Pegaptanib (Macugen) was approved in 2004 for the treatment of macular degeneration and was the first aptamer used in the treatment of any human disease. It is both an anti-vascular endothelial growth factor and an aptamer. Macugen binds to the protein responsible for blood vessel proliferation in the wet form of macular degeneration and inhibits new blood vessel formation. Although antibody treatments soon eclipsed pegaptanib in the macular degeneration field, the therapeutic utility and validity of the peptide aptamer approach has been scientifically proven and can be applied to other diseases.
The company I lead, Regulus Therapeutics (NASDAQ: RGLS), was formed by Isis and Alnylam in 2007. We are leading the charge in the discovery and development of innovative medicines targeting microRNAs. MicroRNAs are non-coding RNAs of approximately 20 to 25 nucleotides in length that regulate gene expression in a remarkable and orderly fashion. Many genes can be regulated by a single microRNA, typically part of the same biological network. Regulus is using a mature platform based on technology that has been developed over 20 years.
To date, more than 500 microRNAs have been identified in the human genome. The identification of disease-specific microRNAs led to the development of oligonucleotide inhibitors of microRNAs or anti-miRs that can modulate the function of microRNAs, leading to the potential treatment of various diseases by restoring normal biological network function. For example, in preclinical models, Regulus discovered that anti-miRs targeting microRNA-21 demonstrated robust efficacy in animal tumor models while anti-miRs targeting microRNA-33a and b have shown great promise for the treatment of cardiovascular disease and metabolic disorders. Separately, Santaris, a Danish biotechnology company, targeted miR-122 in human clinical trials and demonstrated significant viral load declines in patients infected with chronic hepatitis C virus (HCV).
The development of RNA therapeutics is advancing rapidly and the field has reached a tipping point with the approval of mipomersen, the cholesterol-lowering drug from Isis. Given that all four approaches—antisense, RNAi, aptamers and microRNA therapeutics have demonstrated clinical proof of concept and or clinical utility—we expect to witness the dawn of RNA therapeutics and their broad utility to treat human disease in the next several years.
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