Dear all,

Now is the moment when I announce the largest fundraiser in Prion Alliance’s 12-year history: incredibly, donations will be matched up to $105,000 through the end of June. Thank you for considering whether you can help us to meet this ambitious goal! As always, donations can be made through Paypal, or via check mailed to Prion Alliance, PO Box 391953, Cambridge, MA 02139. Thank you!

It’s been a dizzying time. As many of you know, Ionis is now in the clinic with a PrP-lowering ASO: our first shot on goal to lower prion protein levels in the human brain. Given that Eric and I aren’t clinical trialists, clinical neurology professionals or Ionis employees, we have no formal role in this trial. But we are hearing, anecdotally, from people on the ground – people both administering the drug and hoping to receive it. In March, journalist Meredith Wadman published a beautiful portrait of this pivotal moment in our field, visiting a brave family of trial participants and a trial site in Cleveland, and reflecting on her own loss of a dear friend to prion disease just one month before the trial launched.

I’ve written before, and Eric has also blogged about the many, many complexities in any human study, and all of the reasons we most remain attentive and openminded to whatever we learn. With that said, here’s one thing we’ve learned so far that’s both a big deal, and independent of the ASO’s performance: prion disease patients show up. As Ionis shared in a community statement in April, “exceptionally fast enrollment” has actually led them to pause trial enrollment for now. (Ionis clarified is that the pause isn’t due to any data collected, or due to a regulator’s request; the trial continues, and individuals already enrolled are continuing to advance through the process.)

When you go to bat every day for a rare disease, you are constantly fielding some version of the following question: “Will you be able to find the patients?” Well, here’s our answer. Yes, we will.

While they’re not enrolling at this moment, eleven clinical trial sites are now live around the world, spanning the US, Canada, Europe, Israel, and Japan. The stated goal of the trial is to enroll and dose 56 patients. The treatment period is 24 weeks, and the study design is double-blind crossover; all patients, in theory, will receive both drug and placebo injections, but which they receive at which time will be randomized and known neither to the patient nor to the team giving the dose. The study completion date is listed as October 2025. Until then, it is basically the case that no news is good news.

In the meantime, back at the lab everyone’s hard at work (see if you can spot our team of 12 in the picture below). We’ve recently shared two reports on what we’re learning about biomarkers from our ongoing pre-symptomatic natural history study at MGH (here and here). I’ll take a moment to share what we believe is the key takeaway from that second link, a seven-years-in snapshot of our natural history findings. In a sentence: while prion seeding activity may sometimes be detectable in spinal fluid before onset of genetic prion disease, there are limits around the usefulness of this prodromal signal: the window appears short, variable, and genotype-specific. While I hope this finding (and related findings from other labs) will prove clinically useful as we learn more, I will continue to advocate that signs of prion seeding activity, or other pathology, should not be gating for high risk mutation carriers to receive preventive treatment. We can’t count on catching people in this window; and moreoever, even if we could, would we want to wait for prions to be multipling, or for neurons to be dying, before treating a person at known high risk? As you all know, my answer is no.

This is perhaps my favorite soap box, and in April I had the opportunity to haul it right up on the TED stage. The resulting TED talk has just gone live online, and is here. The title: “My quest to cure prion disease — before it’s too late.” In other words, “Our whole deal.”

To share just a bit about the TED experience… First, it was a chance to refect on the incredible privilege of being a person who knows exactly what they want to say. Second, it was a surprisingly rich opportunity to connect with other people who bear the strange mantle of also knowing exactly what they want to say. Even though I was the only biomedical researcher in my cohort, I was moved by the shared intensity that radiated from my fellow speakers, be they champions of nuclear fusion, worker ownership, tools to end extreme poverty, or strategies to fortify democracy. I left with a heightened reverence for how much good work there is to commit oneself to in the world — and for the strange community that is possible among people whose deep commitments point in such necessarily different, yet diversely necessary directions. Humans are amazing.

Speaking of amazing humans, while I was standing on my soapbox in Vancouver an amazing thing happened at home. Daruka, at almost 7, transformed overnight from being a kid who loves being read to and can, technically, read, to being a kid who is reading all the time. Some of you will hear me on how dang near close to impossible it is to not over-identify, in an inappropiately propriety way, with a deeply book-obsessed child. Anyway, I do my best. The words streaming into her stream back out in delightfully transfigured forms. After a big day at school she says with breathless urgency as she runs in the door, “Mom, I have so much things to say. Can I just blast out my words?” At the breakfast table, after losing a tooth, she remarks, “It disturbs me to have a tooth missing. It doesn’t hurt, but it disturbs me.”

And what about Kavari, now a bit over 4? Among other things, he is pioneering the new field of “cute math.” Asked how high he can count, he tells a friend solemnly, “After a million, there are no more letters.” Overhearing someone use the number five, he chirps, “I like five and five. That makes me think of ten!” And here’s a winning if inaccurate dispatch from a recent family foray into “cute epidemiology:”

Daruka: How many germs are there in the whole world?
Me: Wow, I wouldn’t even know how to begin to –
Kavari: Five!

This spring, in the span of two consecutive days, Kavari turned four and I turned forty. The chance adjacency of our birthdays heightens my sense of how linked our timelines are. I’m glad to be able to give these kids, at this moment, the me of middle age – without question the best me so far. And I also walk into this phase of life knowing that for me to see them into their own unfolding future chapters, certain things will need to happen.

Let’s get this done, guys,

With love,
Sonia and Eric