Coming to you LIVE from the 3rd annual RNA Symposium: Advancing RNA Bioscience into Medicine. Follow us on Twitter or the tag #umichrna!

Live blogger: Sarah Kearns. Editor: Whit Froehlich.


Neurodegenerative diseases and genetic conditions lack effective treatments. Patients with disorders like Huntington’s disease (HD) and congenital amyotrophic lateral sclerosis (ALS) thus have unmet medical needs. To begin to get to the heart of these disorders, researchers like Dr. Anastasia Khvorova, a professor at UMass Medical School, are looking for strategies to target RNA in order to develop treatments.

These strategies involve oligonucleotides – small DNA molecules that bind to mRNAs – that can prevent the mRNA from producing that encoded protein. Oligonucleotides by themselves have little clinical relevance because they target their specific mRNA sequences wherever they arise in the body. For diseases that mainly affect certain areas, localization is required for effective treatments. Appending chemical additions or modifications to the backbone of the oligonucleotides allows them to have appropriate distribution and specificity for their target.

Therapeutic oligonucleotides could be the sequence-specific drugs certain genetically determines disorders like HD or congenital ALS need for treatment, and some are in clinical trials. Dr. Khvorova is developing novel oligonucleotide treatments that are safe, durable, and can be widely delivered to the brain and spinal cord.

She is uniquely capable of doing this research and making these oligonucleotides as the founder of the UMass Nucleic Acid Chemistry Core. This is the only nonprofit facility in North America capable of synthesis of modified oligonucleotide in the quantity needed to perform these experiments. She’s also the named inventor on over 150 patents and 200 patent applications, and is defining the field of RNA drug design and development.

Returning to smaller forms of RNA, its unique chemical structure allows it to be a modifiable chemical backbone for drug development. “There is enormous excitement when something is realized” she claims, showing a slide of the Technology Hype Curve showing the market size (and optimism) of using siRNA in clinical contexts. The hype comes from the concept that drugs, instead of being a daily pill, could be administered only once a year as an injectable RNA. What Dr. Khvorova wants to understand is how to effectively use RNA as a treatment and direct its localization to have the desired minimally invasive therapeutics.

We’re now in the plateau of productivity, but many advances continue to be made! Image source.

“Chemistry matters,” she insists, showing the many different types of modifications that are necessary for the stabilization of siRNA. The ribose portion of siRNA in particular needs to be modified so it does not become degraded within the cell. Terminal phosphates, too, will be cleaved instantaneously without chemical protection, where the phosphate is necessary for proper recognition. Modified siRNAs, compared to those that are unmodified, have significantly more stability and long-term tissue retention.

The ribose and phosphate of RNA need to be protected for an effective biologic. Image source.

Trying to address pharmacokinetic properties of the siRNA therapeutic, they turn to co-administering with lipids. Constructing a library of lipophilic conjugates and administering these conjugates with the modified siRNA therapeutics, they found there is better distribution across the body in a mouse model. Looking at two different targets, Huntingtin and cyclophilin B, there is targeted, functional, and selective delivery. This is not contradictory because, while the biologic becomes widely distributed in the body, it is only functional in a certain tissue type where there is aberrant pathophysiology.  

One focus is preeclampsia (PE), the leading cause of premature births, which is caused by oversecretion by the placenta factor sFlt-1; because it has a significant unmet medical need. Levels of sFLT1 mRNA are significantly higher in the placenta than in any other tissue type allowing for an siRNA therapeutic to be a viable option. There are two isoforms of sFlt-1, a short and long construct, where the short form is only found in the placenta and the long form in the mother’s liver and kidney.

A schematic of the role of sFlt-1 in preeclampsia. Image source.

Using the facility of the UMass Nucleic Acid Core, they are able to synthesize and validate the siRNAs for their studies. They find that there is selective sFtl-1 downregulation that does alleviate the hypertension associated with preeclampsia.

Testing siRNA delivery on CNS-related disorders yielded a surprising result. She recounts excitedly alerting her collaborator after the first experiment: “Look, a pink brain!” Dr. Khvorova shows in this pink-colored brain that the siRNA was able to cross the blood-brain barrier, a significant challenge in drug development. Specifically targeting Huntington’s Disease in sheep, she showed that there was sustained modulation of Huntingtin protein expression. With only 2ng of drug per mg of tissue, there can be sustained action and effectiveness of the therapeutic.

Doing the same test in non-human primates, she finishes her talk by showing a very pink brain, with the hope that the siRNA therapy could soon be used in human clinical trials to treat Huntington’s Disease.

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