Dear all,

There is no mistaking these brief, bright, gusty days and frost-breathing nights: we are reaching the close of another year. How lucky are we to be able to announce, yet again, a matching fundraiser to mark the occasion? Your donation will be matched 1:1 up to $45,000 through New Year’s Eve. Thank you for considering a gift to help launch us into the vast and daunting possibilities of 2025.

As we embark on a whirlwind tour of where we’re at, let’s check in first with the Ionis clinical trial. There are now 16 global trial sites enrolled in the PrProfile study designed to test the PrP-lowering ASO ION717 in symptomatic patients. Given swift enrollment, if all goes according to plan the trial may reach primary completion, possibly with an accompanying public announcement, by mid-2025. As a reminder, the primary endpoint of this study is safety but many things about the drug’s activity in the body (amount of drug over time, impact on prion protein levels) are also being measured in the hope of learning as much as possible from this first-in-human study.

We’ve also been hard at work thinking about additional PrP-lowering strategies. To this end, we were able to announce two new programs this year, both of which we’re striving to move forward out of our lab. The first is a divalent siRNA that we are developing in collaboration with Anastasia Khvorova, Julia Alterman and their amazing team at UMass. Like at ASO, an siRNA goes after the prion protein RNA, but its separate mechanism makes it an independent shot on goal. The potency and durability of our lead molecule have inspired us to work to advance it toward the clinic even though we don’t have a pharma partner for this drug; we were lucky to receive a well-tailored award from NIH to support its next chapter. At this point, for the first time, we’ve manufactured a drug product and are awaiting final reports from safety studies to understand if we’ll be able to test it in patients.

The second new strategy, CHARM, is a potential one-time therapy that would work by turning off the prion protein gene. This project is a collaboration in the truest sense with the labs of Jonathan Weissman next door at the Whitehead Institute and Ben Deverman here at the Broad: Jonathan’s team builds the tools to turn off genes, Ben’s team builds the delivery systems to get the drug to neurons, and our team contributes the disease expertise. It’s a rare privilege to combine such diverse complementary toolkits with such single-minded focus; in under two years the proof of concept experiments for this brand-new tool had convinced us to turn our attention to discovering a human candidate. While this discovery process is ongoing, CHARM’s advantages are compelling: by installing potentially permanent marks on the target gene, more so than other strategies we’ve explored it offers the tantalizing prospect of a “one and done” therapeutic strategy.

What is it like to be driving forward drug development projects out of our academic lab? It’s all the things: exhausting, exciting, some days more educational than we can handle. We are learning in-the-weeds details of what it takes to get a molecule to humans that we probably couldn’t have learned any other way.

Where can we imagine this leading? To state the obvious, we are not a drug company. Our ability, as an academic lab, to scale up to future, pivotal clinical trials that would support drug approval, or to provide a long-term supply of the drug to patients, is uncertain. Still, we see several reasons why this academic scale of drug development is worth undertaking. We hope that we will be able to help some number of patients here and now. Even in small clinical studies we will learn things about recruitment, disease course, and biomarkers that we will have the liberty, as academics, to share quickly and broadly with the field. Having our own drug products is a lever for discussion with regulators about key development questions that will be important to our disease community over the long term, including how we pivot to prevention. Finally, as our friend Jordi likes to say, “Data changes minds.” We don’t know what opportunities we’ll see over the next ridge once we have first-in-human data in hand. We have to get there to find out.

And speaking of getting places — in October, Eric traveled to China to attend the international Prion meeting. Over the course of the eleven-day trip he met with Chinese genetic prion disease family members, clinicians, and researchers, and delivered three talks, one of which was fully in Mandarin :0 Trips like this are important as we begin to think about how to broaden the network of sites where future trials might take place, or where future approved drugs might be administered. Prion disease is equal opportunity — though some countries invest more in surveillance, we believe this disease is claiming lives at comparable rates all over the world. Our best future involves drug access for everyone who needs it, and the ability to find as many patients as possible for clinical trials. Now is the time to find our allies.

One other trip to highlight: in November, not long after Eric’s return, we both turned around and participated in a summit organized by the CJD Foundation to explore the connections between prion disease and Alzheimer’s disease and related dementias. It was an opportunity to reflect with a room of scientists and stakeholders on the meaningful ways that the fates of kindred diseases can be linked, even when they are caused by different genes at the root level. While the world is complicated and drug development will never mean only one thing, I do see the story of our now twelve years in science as coinciding with a profound shift in the way the field thinks about therapies. If under the old model each drug was a single-serving “unique beast” with application to one disease, today modular platform technologies and delivery systems have forged links between diseases caused by a single gene — and between those caused by a gain of function — and across those that impact the CNS — all of which we are. My session starred two of my heroes: Ken Chan from the Deverman lab here at Broad, and Holly Kordasiewicz from Ionis Pharmaceuticals. Their tech — viral vectors and oligo drugs for the CNS, respectively — illustrates the story of all boats rising in the most powerful way I can think of. And their commitment takes my breath away. For all that this job asks of me, what it gives me in return is just the best humans.

And how about those other best humans — my small, loud housemates who regularly trash the place and don’t pay rent? They are, as ever, busy being themselves. Here’s a direct quote from Daruka, spoken all in a rush immediately upon bursting in the door from a big day at second grade: “I have unleashed my thinking. Because I have like four imaginary friends and I am making a city for them, I am making like a habitat for them, and I think everyone should unleash their thinking. Just think your own way.”

Noted.

Meanwhile Kavari, now in pre-K, is busy picking up some VERY DISTURBING beliefs which he unveils at random moments that leave me reeling. Like, how did that get in there?? In the spirit of vulnerability I share two recent nuggets:

Kavari: Mom, I always say I’m ok even if I’m not ok. Because I want you to be happy.
Me: OH GOD

Kavari: Doing things by yourself is the best. You know why? Because that means you’re smart.
Me: OH GOD AGAIN

And then, of course, there are the unanswerable questions — because that’s what life is mostly composed of, and sometimes it takes a kid to remind us.

Kavari: Mom, when is the future?
Me: SOONER THAN YOU KNOW

May 2025 surprise you in the best ways.
Be well and we love you!
Sonia