How antisense oligonucleotides are moving from obscurity to a viable drug strategy. Our live coverage of Neuroscience 2019 continues.

How antisense oligonucleotides are moving from obscurity to a viable drug strategy. Our live coverage of Neuroscience 2019 continues.

The first published report on the use of antisense oligonucleotides as a therapeutic agents was in 1978. Researchers at Massachusetts General Hospital were studying a cancer-causing chicken virus that transmits its genetic information via RNA. They noticed that as the virus replicated, its RNA looped around itself. This gave them an idea. What if you could block this step, and stop the bug from replicating? To prove their theory they constructed a short piece of DNA designed to stick to the virus’ single strange of RNA. The RNA encoded the virus’s proteins. They called it the “sense” strand because functionally it made sense.

While the molecular biology being conducted by MGH and other research groups was exciting at the time, translating this technique into successful therapies has been a long time coming. Drug developers have tried using oligonucleotides to treat various diseases, but for none stuck. Some therapies didn’t work, others triggered too much toxicity, while others just didn’t sell well.

Things began to change in 2016, when the US Food and Drug Administration (FDA) approved Spinraza, an oligonucleotide developed by Ionis and Biogen to treat a rare condition known as spinal muscular atrophy. Not only did the drug work well, it breathed new life into the ASO industry, so much so that it’s reached a kind of fever pitch.

So what is the state of ASO therapies today?  How are they being used to rescued ultra-rare N of 1 cases. How does it differ from the hot gene editing tool CRISPR? And are ASOs only relevant for rare genetic diseases?

A Eureka video roundtable discussion probed these questions as Neuroscience 2019 got underway in Chicago, where ASOs were a hot topic of discussion. Moderator Carina Peritore, PhD, Product Manager, Neuroscience Discovery, Charles River interviewed her colleague David Fischer, Executive Director, Charles River Discovery Sciences and an expert in rare diseases.

Dr. Fischer credited the success of Spinraza for opening up the field to the possibilities of ASOs, leading to more recent success stories, such as a drug for a rare case of Batten disease that was recently described this month in the New England Journal of Medicine by Boston Children’s Hospital scientists. The study, which also included researchers from Charles River Laboratories, demonstrated how a customized ASO could be designed, manufactured, tested preclinically, approved and eventually administered to 6-year-old girl with the neurodegenerative disorder Batten disease within 12 months. This unprecedented timetable is seen by some as a model for the future of rare diseases.

“This case was a rare case of a rare disease, a unique mutation that only happened to one child,” said Dr. Fischer. “An (oligonucleotide) was designed within a year form identification of the mutation the patient was being tested with that oligonucleotide.”

While most of the ASOs in development are targeting rare genetic mutations, they are also being eyed for sporadic conditions that are more widespread, though the development path will be different, said Dr. Fischer. “Clearly (these therapies) require a much more traditional discovery and development path than for the Batten case because you are exposing more patients to the therapy and need to understand much more the safety implications.”

Dr. Peritore said it is fascinating to consider that you can take a traditional molecular biology approach with ASOs and then have it move into the clinic, for a single child with Batten disease, so quickly. “How was that able to happen,” she asked Dr. Fischer.

“Dialogue with the FDA was very important,” said Fisher. “It helped toward understanding the absolute minimum required to allow the FDA to progress this therapy to one patient and how to understand the potential safety liabilities of the drug. In light of the rapid progression of this disease we didn’t have time to waste here.”

During Neuroscience 2019, drop by Booth 1043 to learn more about how Charles River is studying neuroinflammation, and other hot CNS topics. And follow the conversation on Eureka, Charles River’s science blog.