RNA Therapeutics Are Coming of Age


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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.

RNAi Therapeutics

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.

microRNA Therapeutics

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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Kleanthis G. Xanthopoulos, Ph.D. is the former president and CEO of Regulus Therapeutics, a company developing drugs based on microRNA technology. Follow @

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3 responses to “RNA Therapeutics Are Coming of Age”

  1. Kyle Smith says:

    why NO mention of delivery RNAI stocks TKMR or ARWR

    • Kevin CC says:

      Because author has ties with Regulus which is tight with ALNY which is not tight with TKMR to say the least.

  2. miRNAblog says:

    “To date, more than 500 microRNAs have been identified in the human genome.”

    This number is rather outdated. Since 2007 there are more than 500 human miRNAs known. Currently, there >2000 human microRNAs validated and listed in the public data base miRBase.org .