Dear all,

The outset of another summer! I’m humbled to share that matching donors are yet again stepping up to help us launch with confidence into the second half of the year. Donations will be matched up to $105,000 through the end of June. Thank you for donating or considering donating, now or in the past or in the future! It matters.

There is, as always in this quest, lots to say and lots to do, lots to be grateful for and also lots to power through. The bottom line is that it’s all moving forward, everything, even when this feeling isn’t topmost in the great big stack of feelings. Depending on the day, for me tuning into our momentum takes a certain shift in focus, a conscious choice to step out and back, kind of like seeing a magic eye. In the words of David Stendl-Rast, “How I perceive such things is a matter of spiritual discipline.” It’s a real art, seeing what’s there. I’m not always good at it, but I’m learning.

Diving into our blitz of updates, let’s work from the clinic backwards. Ionis’s trial, PrProfile, has finished enrolling and is now following dosed patients out to end of study this summer. This doesn’t mean there will be data right away — many analyses are batched together at the end of the study, and these all are done with a level of stringency and documentation that is completely unlike a typical research lab. But perhaps by the end of the year we can hope to hear from them an update on what we’ve learned.

Also in the bucket of updates we may be able to hope for in the near term: let’s talk about our PrP-lowering divalent siRNA. The last time we wrote, we had drug vials of divalent-siRNA ready for dosing and were waiting on safety reports. To make a very long story short, the reports were all encouraging, and fed into a heroic effort, led by Eric, to compile a 3593-page PDF: our first lab-led Investigational New Drug application. The IND was filed with FDA in February, and in March we learned that we had received clearance to dose a small number of symptomatic patients (15) with this brand-new drug. Meanwhile, a long-uncertain piece of the puzzle appears to be falling into place: through a mechanism called NeuroNEXT, NIH looks likely to fund this first-in-human trial.

So what happens next? Hoping we receive official notice of the NeuroNEXT award this month, setup activities will then begin at clinical sites. Again, the things you only learn by doing — apparently this is a complex undertaking and takes several months. But if all goes reasonably according to plan, our ambition may be to dose a first patient by early 2026.

You can read more about all of the above on Eric’s blog, and if you’re so inclined you can even read the whole 3593-page IND, which we’ve made public. Sent out into the world with our usual prayer: may it be helpful to someone.

So, was this an unmitigated success story? Well, in this universe, no such thing — and also, in truth, the di-siRNA story has only just begun. The scope of this first study is modest — we are cleared to dose 15 symptomatic patients, one time. To be able to give periodic doses to maintain PrP suppression over time we will be required to complete a longer multi-dose safety study. In addition, FDA has mandated us to do a primate safety study to unlock dosing of presymptomatic individuals at risk. None of this is a no — it’s all a path forward — but it also all takes time. So, as usual, both things are true – tons to celebrate and tons still to do.

Day to day in the lab, our fabulous team of fourteen continues to advance a raft of other projects. We were able to share a few of these for the first time earlier this year, including a base-editing collaboration with David Liu’s lab, and a zinc-finger repressor project with Sangamo Therapeutics. We continue to push forward AAV-CHARM, our lab’s home-grown gene therapy project which, like the di-siRNA, has very much thrown us into the deep end. We’re lucky to have the support of the NIH Somatic Cell Genome Editing (SCGE) consortium, through which we meet regularly with a small set of like-minded teams who are also trying to build rare disease gene therapies out of academic labs and who, movingly, care as much as we do. This special group includes Kiran Musunuru and Becca Ahrens-Nicklas, who recently developed a record speed N-of-1 gene-editing therapy for Baby KJ. The longer we’re at this, the more the solidarity of fellow travelers — and the privilege of witnessing their successes — turn out to be my most important sources of fuel.

Speaking of fellow travelers: a quick snapshot of the other humans in my house. To my delight, with Kavari now age 5 and Daruka almost 8, our family has entered the era of “would you rather.” In case you’re in search of a dilemma to chew on, below are some recent favorites:

Kavari: Would you rather have ten hundred dumb bunnies or one crocodile that will eat you?
Me: …Will it definitely eat me?
Kavari: It will definitely eat you.

Daruka: Would you rather have ten hundred puppies or unlimited power?

In total frankness, in the course of the daily routine many things about parenting wear me out. But I never tire of the kids’ questions, or the innately poetic way they relate to language in general — the easy borderless way they slide between the comic and the cosmic. The other day as he was stepping into the bath Kavari asked me, “Mom, will you go with me to the edge?” When I asked, “The edge of what?” he answered solemnly, “The edge of where we are people and things.” A few nights later I was stroking Daruka’s hair as she fluttered towards sleep. For one moment she semi-awakened, looked me in the eye and said dreamily: “Pancakes and waffles, the moon, and you.” A moment later her breath was rhythmic as I tiptoed from her room.

I recently wrote a letter to our friend Adam with the urgent-feeling goal of conveying a bit of what life feels like to me right now. Like with all daunting tasks I just had to start somewhere — jump in on some random note and go, without presuming to plan or assuming that I would or could succeed. And indeed, I wrote for some unknown amount of time fairly convinced that I was failing. But at the very end, I managed to say this:

There’s so much to do, to think about, be, stand for, try to make sense of, dream about, feel torn apart by, grieve, fight for, love. This is my main feeling, and I feel it all the time.

And I briefly experienced that rare serenity of having said, or at least kind of said, what I meant to say.

Thank you for being with us through all of the things!

with love,
Sonia