Ionis Pharmaceuticals Publishes Paper on Growth of RNA-targeted Therapeutics in Cell Metabolism

RNA-targeted therapeutics come of age as a platform for drug discovery across disease states-

-Stanley Crooke, M.D., Ph.D., is the architect of Ionis’ antisense platform – the most efficient, productive and broadest RNA-targeting therapy –

Today a review highlighting the current status of RNA-targeted drug technology, including various opportunities and challenges was published in Cell Metabolism, a prestigious journal focused on the communication of strong, engaging science. The paper titled, “RNA-targeted Therapeutics” was authored by Stanley Crooke, M.D., Ph.D., the founder, chairman and CEO of Ionis Pharmaceuticals and provides an overview of the Ionis antisense platform compared to other RNA-targeting platforms. Dr. Crooke’s three decades spent advancing the science of antisense technology has allowed scientists at Ionis and in other organizations to more efficiently and effectively use antisense drugs and other RNA-targeting therapeutics for a wide range of diseases. In December 2016, SPINRAZA became the first RNA-targeted medicine approved for the treatment of children and adults with spinal muscular atrophy (SMA), a rare and sometimes fatal disease. It also was the fourth RNA-targeted therapy to be approved by the U.S. Food and Drug Administration. Today, three additional RNA-targeted drugs, including inotersen and volanesorsen, are under regulatory review and more than forty others are rapidly advancing through the Ionis pipeline alone.

In this review, Dr. Crooke provides an insight into the contributions he and his colleagues at Ionis have made in understanding antisense technology and this growing class of therapeutics. Specifically, the distinct differences in delivery, efficacy and safety of each medicine. Dr. Crooke highlights the importance of structure, chemistry, pharmacokinetics, medicinal chemistry, and performance in clinical studies for the development of various chemistries of antisense drugs, small interfering RNAs (siRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acid antisense drugs (LNAs).

The single-stranded structure of antisense drugs facilitates optimal cell uptake and distribution, allowing for a variety of routes of administration. Importantly, he notes that because members of the same chemical class have minimal differences in sequence, they share similar pharmacokinetic profiles and biological properties, allowing Dr. Crooke and his colleagues to predict the outcomes of studies of various antisense drugs. While he says that off-target hybridization and unexpected outcomes can and do occur, antisense drugs “have proven to be remarkably specific.” As medicinal chemistry continues to advance, Dr. Crooke points to enhanced potency and pharmacokinetics and potentially impeccable safety for antisense drugs entering development, namely the N-acetylgalactosamine (GalNAcs) – a Ligand Conjugated Antisense drug, or LICA. Using the aforementioned areas as a metric for comparison, he concludes that the antisense platform has proven to be a much more valuable and productive RNA-targeting therapy compared to others, like RNAi.

While Dr. Crooke and his colleagues will continue to advance the chemistries and better understand the science, the concept of RNA as a therapeutic target and new class of medicines has been realized. This review underscores the importance of RNA-targeted therapeutics, which are on the verge of becoming an important platform in the development of medicines across a broad range of diseases from cardiovascular disease to neurodegenerative diseases, such as Huntington’s disease, from rare diseases such as acromegaly to diseases affecting millions, like cancer, and many more. RNA-targeted therapies have come of age.


  1. Crooke et al., Cell Metabolism, Online Publication, April 3, 2018; link: