For the past five years, Eric and I have been working with Ionis Pharmaceuticals on the strategy of using an antisense oligonucleotide, or ASO, to lower the amount of prion protein in the brain, as a way to treat, delay or prevent prion disease. You can read about the rationale for this therapeutic approach, and why we’re optimistic, here.
One of our biggest jobs in evaluating ASOs for prion disease has been to conduct efficacy studies in prion-infected mice. The big question here is simply: do treated animals live longer than untreated animals? Of course there are many different ways to get at this question, so this has been a long road of experiments, but this past week marked an important milestone: our first set of ASO survival studies is now officially published.
Learning how to do these sorts of therapeutic studies was a steep learning curve for Eric and I, but luckily we weren’t alone: Dr. Byron Caughey and his group out at Rocky Mountain Labs, including Greg Raymond, Lynne Raymond, Brent Race, and Katie Williams, were long-time veterans of prion mouse studies and stepped up to help get these studies off the ground while Eric and I got set up at the Broad Institute. This approach had the advantage that our first studies testing ASOs in prion-infected mice were replicated at two independent sites, by different sets of hands, using slightly different experimental details. Excitingly, what we learned is that ASOs are effective against prion disease in mice.
Breaking it down in slightly more detail, here are three main findings. We learned that the beneficial effect of ASOs is mediated by their ability to sequence-specifically target the PrP RNA and reduce its levels; an ASO with a random sequence doesn’t impact disease. We learned that when administered prophylactically, before prion infection, even just two doses of an active ASO can potently delay onset of symptoms, extending healthy life. We also tested a later treatment, administering a single dose of ASO just before frank symptom onset, when the animals’ brains already showed signs of prion-related damage. One of the two tested ASOs still extended life at this later timepoint, partly by slowing down the progression to end-stage disease once symptoms had begun.
So what comes next? There are many more mouse studies in the pipeline, testing ASOs against different prion strains, at different doses, and at a wider range of treatment timepoints. This May, at the Prion 2019 meeting in Edmonton, Alberta, I had the opportunity to present a lot of these additional data, and you can read Eric’s notes from that talk. In the coming months, we’ll be working on preparing a next manuscript to share more of these findings.
In the meantime, though, this is a great moment to pause and reflect on just how many people came together to make these studies a reality. Byron’s lab and our partners at Ionis did an amazing amount of work. Jason Le, Sam Graffam, and the rest of the Comparative Medicine team at the Broad Institute were heroes to our animals. Deb Cabin and Curt Mazur both flew out to Boston to train us hands-on. Jeff Carroll at Western Washington University has been an instrumental advisor from day one of our ASO journey. Finally, a special thanks goes out to CJD Foundation — in 2016 they awarded a grant to Byron’s lab that allowed us to get the first ASO mouse studies up and running.
There’s still a lot to learn and a lot to do, but we are excited about where the data are taking us. Stay tuned for more on ASOs for prion disease.