First: how to help us power our engine. I am grateful to share that donations to Prion Alliance will be generously matched up to $15,000 through the end of the year. As usual, donations can be made through PayPal, or via check mailed to Prion Alliance, PO Box 391953, Cambridge, MA 02139. Thank you for helping us fight the good fight!
Second: a long-awaited update! The first human clinical trial of a prion protein-lowering drug has now officially posted to ClinicalTrials.gov. This listing tells us that Ionis’s trial of an ASO for prion disease is nearly ready to begin at at least one trial site, congruent with what we’ve heard from a number of different sites around the world. The listing also shares some details of the trial, such as that it will aim to recruit on the order of 56 symptomatic patients who are experiencing early-stage prion disease. There’s also plenty of detail not yet included, such as where the clinical trial sites will be. You can read Eric’s post for further color on what we know at this point.
Without jinxing it — this is a hard-won milestone! And at the very same time it’s a summons — a cueing up of work yet to do. I see pros and cons to doing this first trial in symptomatic patients. In this first stage, the goal is simply to determine a dose level that is safe enough and lowers the protein enough. A next stage may ask whether the drug moves disease biomarkers or brain imaging in the right direction, maybe even whether it influences the rate of disease progression. But trials in symptomatic patients will never tell us whether a PrP-lowering ASO could have prevented or delayed onset in the first place, if administered before symptoms. This question remains to be explored in separate trials, for which we will continue to advocate.
It’s an unthinkable amount of work to get a first human study off the ground, and to me it seems inevitable that the initial study won’t be able to answer every question. I know our allies at Ionis thought long and hard about how to structure this first clincial experience, and I’m grateful to be at this point. And at the same time, moving forward I think it will be more important than ever to remember that in an undertaking as complex as developing a meaningful treatment for prion disease, no one outcome represents success or failure — including how this first trial goes. All year I’ve found myself telling audiences about the Stockdale Paradox. Some of you may know this story (or may have already heard it from me!) but it merits retelling, as I have never had such an eerie sense that someone else’s words so perfectly captured one of my core values — in this case, grounded optimism. Admiral James Stockdale was held as a prisoner of war in Vietnam for seven years. After his release, he was asked what set apart those who survived captivity from those who didn’t. He answered that prisoners who clung too tightly to the idea that they’d be out by Christmas, or any other particular date, didn’t make it. And he said this:
You must never confuse faith that you will prevail in the end — which you can never afford to lose — with the discipline to confront the most brutal facts of your current reality, whatever they might be.
No matter what we learn, there will still be more work to do. And there will still be, as we move forward through time, more reason than ever for hope.
So speaking of the work to do — who exactly is doing it? Here in the lab we’ve had another growth spurt this year, and are now 12 people strong. It’s been a huge learning curve for Eric and I as we’ve transitioned from generally having the pulse of every project and a sense of how everyone’s doing, to seeing only the high level and needing to delegate all the details. We still have lots of learning to do, and likely always will, around balancing growth with laser focus.
In October, we hit a work/family milestone when I traveled to Europe for 9 days of conferences, heroically enabled by Eric soloing the kids (with grandparental support — thank you Dad and Pinni!) This length of trip hadn’t seemed possible at any prior point since Kavari was born, but I’m glad we’re experimenting to learn how our capabilities are shifting with time. My time in Barcelona, at the Oligonucleotide Therapuetic Society annual meeting, was particularly rich. It was my first time attending this conference in person, and we were given a tremendous platform — very much on behalf of the team, I was honored to receive the society’s Best Paper of the Year award. Above and beyond winning prizes though — the dynamic in the group of roughly 800 scientists was electric. The word “therapeutics” is in the name of their collective identity, and I could feel it. I looked out over the sea of faces thinking: many of the people who will be involved in curing brain disease over the next ten years are sitting right here. To have the chance to walk up on stage and remind them about prion disease, and about prevention, and to challenge them to ask what they would want for their own brains, or the brains they love best in the world — well, it was pretty cool.
This fall I also had the pleasure to speak with Maya Shankar on her podcast, A Slight Change of Plans. The episode, “The Coin Toss”, ended up being a more personal take on our journey than what usually makes the airwaves, and I’m grateful to have had the chance to circle back through some of our personal history and see it with the eyes of my nearly forty-year-old present self. Among other themes that this conversation ended up evoking for me, there’s so much that is still evolving in my relationship with my mom, as I move through different ages and stages that I watched her live. I’m now at a stage in my parenting journey that I can remember being on the other side of, with her. I sit at our kitchen table with Daruka, now a six-year-old first-grader, and we make art together the way my mom and I did. And I remember in my body the awe I felt at my mom’s sure hand, at her daring choices and asymmetical flourishes. Vertigo is not too strong a word for what I feel when Daruka’s eyes rake over my page with that same intimate and mystified longing.
Speaking of Daruka, and my mom — this year his year Daruka was finally old enough to attend an event she has long coveted: Bring your Little Broadie to Work Day. A souvenir Eppendorf tube of triumphantly extracted strawberry DNA, strung on a rainbow lanyard in her bedroom, bears testament to the special place this event has in her heart. At some point between science activities and general romping around, she was interviewed by the organizers about her relationship to the Broad. Here’s an excerpt:
Interviewer: Do you know what your mom and dad do at the Broad? What do they do for work?
Daruka: Um, Um, they try to, they try to solve a special, um, thing that my mom’s mom got um, and made her die.
Interviewer: That’s pretty cool, isn’t it? I think that’s pretty cool.
[Daruka smiles with pride despite herself]
Interviewer: What do you think when your mom and dad come to work, what do you think they’re doing all day?
Daruka: Doing what they usually do and sometimes they, um, they give talks…. and I think they mostly work on computers. Most work involves computers!
Interviewer: That’s probably true, I think that’s right!… What do you think science is?
Daruka: Science is where you study things and study objects and you can learn and you can, um, explore and find your way.
She is so of our family, and also so her own person, making sense of her world. It breaks my mind that the two can both be so fully true.
Did I mention she was clutching a stuffed ram the whole time?
Then there’s the little guy. For Kavari, now age 3.5, the joyful neurological explosion that is development manifests daily as constant chatter. Equipped with Legos and trucks and maybe a bit of string or rubber band, he has everything he needs to improvise a small world and narrate its creation myth and concerns, monologuing for an hour or more. In verbalizing his world and wants to us, he persistently, colorfully throws himself into the task.
Here’s a recent exchange from our dinner table:
Kavari: I want to throw up this chicken.
Kavari: I want to blow up this chicken.
Kavari: I want to cut up this chicken.
We build bots and call what they’ve got intelligence. We draw reductionist diagrams of the human body and label the brain as it it were just another organ. But it’s not — and as if I needed proof, here I’ve got these kids.
Thank you for believing in us — and here’s to another year of learning.
Sonia and Eric