It is an RNA world

RNA-based molecules have redefined the universe of tractable targets by putting virtually anything that is gene encoded within reach of a disease-modifying agent. This redefinition has launched RNA as the biotech industry's third drug modality.

The emergence of noncoding RNAs presents yet further opportunities for the modality, but a rudimentary understanding of the bioactivities of these molecules, the delivery hurdles and the difficulties of target selection and validation still surround this new therapeutic class.

A think tank convened by SciBX that comprised academic, biotech, pharma and VC stakeholders surveyed the state of the noncoding RNA space. The key opinion leaders laid out a road map for developing and implementing RNA therapeutics and for exploiting the molecules-which include long noncoding RNAs (lncRNAs) and microRNAs-as disease targets.

"With small molecules, there is an undruggable or at least difficult to drug set of targets. A second modality, of course, is biologics-antibodies and so forth. But there are still a lot of targets that we would like to go after that we cannot drug with those approaches. And that is where RNA and oligonucleotides come in. In principle, there is no undruggable target anymore," said panelist Aimee Jackson. She is director of target development at miRagen Therapeutics Inc., which is developing anti-miRNAs.

For the near term, the think tank recommended that drug developers prioritize diseases for which there is solid knowledge of the human genetic underpinning and focus on strategically selecting RNA targets based on how accessible they are in humans. In particular, to avoid clinical setbacks caused by poor target selection, the key opinion leaders emphasized the importance of identifying reliable biomarkers and developing target engagement assays for clinical studies.

For the long term, the panel outlined activities that will be needed to gain a comprehensive understanding of the biology of emerging classes of noncoding RNAs. In addition, it pressed for new delivery agents such as conjugates or particle formulations that expand the repertoire of accessible tissues and improve intracellular release of therapeutics following endocytosis.

Thus, for the second straight year, endocytosis was called out as a black box that impedes drug delivery. The 2012 SciBX Summit, which focused on macrocycles and constrained peptides, also stressed the need for translational studies on endocytosis.1

In addition to Jackson, the think tank consisted of David Corey, Jean-François Formela, Art Krieg, John Maraganore and Laura Sepp-Lorenzino.

Corey is a professor of pharmacology and biochemistry at The University of Texas Southwestern Medical Center and has been exploring oligonucleotide-based therapeutics and RNA targets for more than 20 years. Formela is a partner in the life sciences group at Atlas Venture and a cofounder of RaNA Therapeutics Inc., which is developing molecules to upregulate gene expression by targeting lncRNA. At the time of the meeting, Krieg was CEO of RaNA. Most recently, he was SVP and CSO at Sarepta Therapeutics Inc., which develops RNA-based therapeutics targeting mature or precursor mRNAs to turn gene expression on or off. He departed that position earlier this week.Maraganore is CEO of Alnylam Pharmaceuticals Inc., which develops therapeutics based on RNAi. Sepp-Lorenzino is VP and an entrepreneur in residence at Alnylam. At the time of the summit, she was executive director of RNA therapeutics discovery biology at Merck & Co. Inc.

According to Formela, "The conjunction of the maturation of the modality, the explosion of the biology and the focus of the industry and of the capital market on trying to solve orphan disease has created a perfect opportunity for investors."

Maraganore said that numerous advances have minimized some of the early negatives associated with RNA therapeutics, including undesirable toxicity or immune system activation.

Formela added that in terms of toxicology, therapeutic RNAs are becoming more like small molecules. "If we end up with a platform that is just as good-maybe better in terms of time to development of a candidate because the design on the front end is much more rational than the design of a small molecule-I think it will be a very attractive platform," he said.

RNA buzz

There has been a steady increase in investment in oligonucleotide-based therapeutics over the past three years, including a surge early this year (see "2014 first-quarter industry activity in RNA therapeutics").2

More than $1 billion was invested in the RNA space during 1Q14, headlined by Alnylam receiving a $700 million equity investment from the Genzyme Corp. unit of Sanofi that expanded the strategic alliance between the companies.

Genzyme obtained global rights to commercialize Alnylam's lead compound, patisiran, outside the U.S. and Western Europe. The expansion added three additional molecules from Alnylam's pipeline to the alliance. Until 2020, Genzyme has the option to co-develop and commercialize outside the U.S. and Western Europe all rare genetic disease therapeutics in Alnylam's pipeline.

Other big deals include Alnylam's acquisition of Sirna Therapeutics Inc. from Merck for $75 million up front plus milestones and Moderna Therapeutics Inc.'s $100 million deal with Alexion Pharmaceuticals Inc. to develop messenger RNA-based therapeutics in rare disease.

On the finance side, Dicerna Pharmaceuticals Inc. raised $90 million in a January IPO.

Also that month, the Life Technologies Corp. The goal is to release 65,000 siRNA sequences targeting more than 20,000 human genes. New data generated from the initiative will be added to PubChem on an ongoing basis, making the database a resource for the RNA community.

In fact, investment in basic research and resources

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