Prion Alliance

First-in-human trial of PrP-siRNA in symptomatic prion disease

Wed, 22 Apr 2026 12:01:00 +0000

We are proud to announce the launch of a first-in-human clinical trial of a new drug candidate for prion disease. The investigational drug is a divalent siRNA called PrP-siRNA, which is administered intrathecally — meaning, by a lumbar puncture — and is designed to reduce the amount of prion protein (or PrP) the brain produces. We do not yet know if PrP-siRNA is safe or effective. The goal of this clinical trial is to gather the very first human safety data to inform dosing and determine whether PrP-siRNA should advance to larger trials that would evaluate safety as well as efficacy in a larger cohort of patients.

Who developed this drug, and who is sponsoring this clinical trial?

PrP-siRNA was developed starting in 2020 as a collaboration between our lab at the Broad Institute and Anastasia Khvorova’s lab at UMass Medical School. The project utilized funding from two National Institutes of Health grants (the IGNITE and URGenT programs) as well as from families and members of our patient community who donated either to Prion Alliance or to the Broad Institute. The official sponsor of this clinical trial is the Broad Institute, and the trial is being paid for by a National Institutes of Health program called NeuroNEXT.

What is PrP-siRNA designed to do?

We described research and development of PrP-siRNA in detail in a publication from our lab [Gentile 2024]. PrP-siRNA is a short interfering RNA (siRNA), and has a sequence of A, C, G, and U letters that is designed to target the RNA molecule in our cells that contains instructions to make PrP. PrP is the normal protein that, in disease, misfolds and becomes a pathogenic prion. We and others have hypothesized that reducing the amount of PrP in the brain will slow the progression of prion disease. To achieve this, we have designed PrP-siRNA to such that when it finds its target RNA, the cell cuts the target RNA up and produces less PrP.

PrP-siRNA has so far been evaluated only in animals, however — this trial will be the first time it has ever been administered to humans. There are not yet any human data to indicate that PrP-siRNA will benefit patients.

What is the goal of the study?

The goal of this trial is to evaluate multiple dose levels of PrP-siRNA in a small number of patients. We will evaluate the safety of the investigational drug at each dose level, as well as measuring PrP in spinal fluid to determine whether the drug appears to be lowering PrP in the brain. We hope that results from this trial will help us to determine whether PrP-siRNA is safe enough to justify testing in a larger number of patients and determine whether it does what it was designed to do. Depending on the answers, the results from this trial could help to motivate a larger future clinical trial of this investigational drug.

Who is eligible to participate?

You may be eligible for this study if you meet all of the following criteria:

experiencing symptoms of prion disease
have been diagnosed with prion disease by a physician, with either a positive RT-QuIC test or a positive genetic test for a PrP mutation
still only mildly or moderately impaired
have a caregiver able to accompany you to all study visits
18 years of age or older

Additional criteria apply, and will be evaluated at screening.

What does participation involve?

Participants will be admitted to the hospital overnight, will receive an intrathecal (lumbar puncture) injection of the study drug, and will make in-person follow-up visits to the clinic 1, 2, 4, 8, 12, and 24 weeks afterwards. Some follow-up visits will include additional lumbar punctures, MRI scans, blood draws, cognitive testing and in some cases a CT scan.

At certain times, for example while awaiting data that would permit us to escalate to a new dose level, we may be unable to enroll patients in the drug treatment study. If you approach a study site for screening during one of these times, you may be offered the option to enroll in an observational arm of the study. Participants in the observational arm will not receive PrP-siRNA, but will make an in-person baseline visit as well as follow-up visits 4 and 8 weeks afterwards. The data from the observational arm will help us to determine whether the drug is having an effect in the treatment arm. If, while you are participating in the observational arm, enrollment in the treatment arm is re-started, you may be offered an opportunity to switch to the treatment arm, but this cannot be guaranteed.

Who should I contact to learn more or volunteer?

You can read additional details of this trial on its ClinicalTrials.gov posting. If you wish to be screened for possible enrollment, you can reach out to the study site nearest you, or you can contact priontrials@broadinstitute.org

The only way is to show up

Tue, 09 Dec 2025 12:01:00 +0000

Dear everyone,

I’m grateful to be able to share with you yet another fabulous act of end-of-year generosity: your donation will be matched up to $50,000 through December 31. As our science life becomes larger + stranger (and it only ever seems to move in this direction), the flexibility of donated dollars compared to other funding sources – the ways they allow us to act quickly on new information, and to circumvent delays – only matter more. Thank you for powering us to chase the mission at full speed.

Now is when I say stuff about where things are at. And this turns out to be an invitation to reflect on the different kinds of time – the very different things that six months can mean, across contexts in which we operate. There’s a certain kind of time dilation that happens as drug development programs approach and enter the clinic, and I’m still working to understand all the contributors, which are worthy and which are not, which can be compressed with great effort, and which can’t. It is, like everything I guess, a lived experience of the serenity prayer.

Six months since our last update, we remain in a holding pattern awaiting news from Ionis’s first-in-human trial, PrProfile. We hope some news of trial outcomes will come soon, and we hope more specifically that Ionis will choose to share both safety and target engagement data from this study – enough to perhaps gain a first glimpse at the disease modifying potential of this one particular drug. Ionis has already set an important precedent of openness by sharing a manual for the clinical rating scale used in the study, and for this we applaud them. Families participating in the trial have told us that they are doing so less for any prospect of direct benefit, and more as a contribution to research, to help those to come. To best honor their generosity, we have been steadily advocating for sponsors to publicly share individual patient data from all clinical trials in prion disease, and that is exactly what we plan to do in our own trial, of PrP-lowering divalent siRNA, beginning next year.

The update on that front: in August we received notice of funding for our first-in-human di-siRNA trial, from an NIH program called NeuroNEXT. Since then, we’ve been in the process of getting five clinical sites set up with the right trainings, permissions, protocols, and paperwork to begin recruiting patients. It remains possible that we will dose a first patient in the opening months of 2026. I hope that this will happen in under one year from when our IND was cleared by FDA in March 2025. I am working to understand why this process has taken the better part of a year, and what from this experience, both in terms of infrastructure and our own knowledge, can be paid forward to make the next time faster.

As I mentioned last time, the scope of this first clinical study is modest, and we are thinking hard about how to expand into pre-symptomatic individuals at risk – very much an ongoing conversation with FDA – and how to ultimately pivot from single to repeat dosing. As demanding a journey as it has been to lead our own drug development programs out of the lab, I feel grateful to have “one of each” – one oligonucleotide therapy at the threshold of the clinic, and one gene therapy coming up behind it – to serve as our own levers to drive regulatory conversations about how we think about risk-benefit, trial design, and meaningful outcomes in prion disease. We have a freedom that many company sponsors don’t feel they have to push these conversations away from the status quo, and toward something that better reflects the totally unique biology and constraints, the particular horrors, frankly, of our disease. This freedom is, for all that we’re a shoestring operation cute on budget and long on spirit, a form of power. And with great power comes great responsibility.

I think a lot these days about how to square the absolute specificity of biology with the human systems, such as FDA and IRBs, in whom we entrust decision-making authority over how and in whom drugs can be tested. Thinly resourced systems taxed with high levels of diverse throughput, which will naturally seek to streamline the cornucopia of human disease biology into generalizable principles, templates and precedent. I suspect that maybe the only real way to bridge these worlds is to show up, in person, with your opinions and your rollaboard. Ideally also an eye-catching jacket and a few good jokes, for winning hearts and minds. So I’ve become a bit of a human pinball, pinging most often to D.C. but also to other cities and stages, trying to remind everyone as best I can that of course, the longer we spend inside any human system, the more its workings seem inevitable. Of course, we have default settings for how we think about risk-benefit, the contents of a drug safety package, how long it takes to get into the clinic, who belongs in a trial. Of course, daily delays and frustrations and shortfalls seem like just the way it is. But it is our job – all of our job – to notice the mirage of inevitability, and call it to account. If law school taught me one thing, it’s that we totally made up our human systems. If they’re not working, it’s our job to change them.

Back at the ranch, our team of seventeen is hard at work honing additional therapeutic shots on goal, gathering and analyzing clinical datasets, and building out our understanding of prion protein biology. On the home-grown gene therapy front, we’ve reached an exciting inflection point – after years of engineering and testing different versions of CHARM, our PrP-lowering epigenetic editor, we are now at the stage of selecting a human candidate. The psychological challenge here is to commit to locking a version of the drug that we will move toward the clinic, while also knowing for sure that further engineering could continue to improve the molecule in basically every way. This exercise is excruciating, and has deepened my empathy for sponsors of new medicines in general, all of whom struggle with some version of this universal tradeoff between a good thing sooner, and a better thing later. I truly hope we will manage to resource both efforts – the push to bring version 1 to first-in-human within the next two years, and the continued work to mature version 2. We continue to be deeply fortunate that NIH, through the Somatic Cell Gene Editing consortium, has bet big on version 1 and will fund the “IND-enabling studies” – large-scale manufacturing and characterization, FDA-facing safety studies – that academic labs are almost never in a position to run themselves. I had the opportunity to visit NIH last week and to thank them for this investment in us, and to tell them how I think about paying it forward: by moving fast. By sharing everything. By de-risking new drug types in the brain that may prove useful for diseases beyond ours. I’m humbled by the partnership of our NIH program officers, who have fought to make these specific translational mechanisms a reality, and are driven to stay in tough jobs by their commitment to seeing this work through to patients. One antidote to human systems malaise is to spend time with those special individuals who are wide awake inside the systems, fighting the good fight alongside us.

For all of these different workstreams, we continue to be beyond lucky to call the Broad Institute our home base. Earlier this year we were greenlighted to move to a larger space on the other side of the building. Umpteen crates and spreadsheets and cleanouts later (thank you team!) the dust is now settling in our new digs. Our offices, previously split across two floors, are together. Our prion room, previously rate limiting, is 3x its former size. And as a bonus, our new space is communally oriented in a way that our old space was not. The details are so simple: a centrally located common space, tables, chairs, kitchenette. A plant. Nothing fancy. And yet: the frequency of incidental interaction has gone up, the barriers to intentional interaction have gone down. Life feels like a slightly more densely woven conversation: more productive, more surprising, more lovely. It’s a specific professional incarnation of a core belief I hold more generally: that if we can find our way past our million silly hesitations, our forest of obstacles real and imagined, we really do want to be more a part of each other’s lives.

I usually close with a dispatch from the kids, a custom that I fear makes family life seem redemptive and idyllic. I promise it’s also messy, fractious and loud! I mourn the amount of friction that emanates from the daily routine, the amount of energy that’s sunk into the mundane paces of getting out the door or getting to bed. For me, the best and only antidote is surprise – the moments when the kids serve as my best reminders that nothing in this world is scripted, or remotely predictable. Like Kai Kai, now 5.5, turning his enormous eyes on me at point blank range to ask, “Am I myself, Mama? And not an atom different?”

Or Daruka, age 8, reflecting as she gazes out from our front balcony, “Every single person and thing in the world is different. Not a single thing is the same as anything else. Isn’t it beautiful?”

To which the answers are yes, and yes – and also some larger YES to the epic undertaken of living this life together, even when nothing about it is simple.

Wishing you a year rich in connection and worthy challenge.
with love,
Sonia

All of the things

Mon, 09 Jun 2025 12:01:00 +0000

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

When is the future?

Mon, 02 Dec 2024 12:01:00 +0000

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

A crazy moment in a crazy journey

Thu, 30 May 2024 12:01:00 +0000

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

Marching forward onto new terrain

Tue, 05 Dec 2023 12:01:00 +0000

Dear all,

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.
Me: ?
Kavari: I want to blow up this chicken.
Me: ?
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.

with love,

Sonia and Eric

Mid-year update

Thu, 01 Jun 2023 12:01:00 +0000

Dear all,

First, the business of powering the mission. I am thrilled to share that donations to Prion Alliance will be generously matched up to $60,000 through the end of June. As usual, donations can be made through PayPal, or via check mailed to Prion Alliance, PO Box 391953, Cambridge, MA 02139. Thank you for supporting us to do the most important things, as soon as we realize they are the most important things! The longer we’re at this the more we appreciate that flexibility, as much as dollars, has been the rare gift of your donations.

Last December, I shared some of my concerns about the pace at which prospective drugs advance from the “wow, this has a reasonable chance to really help people” stage to the “here we are dosing a real individual human whose real individual, unimaginably complex and unrepeatably unique life may be impacted” stage. Well, since we last talked I haven’t fixed the problem, and my feelings are no less mixed. While we continue to see promising signs of Ionis’s continued commitment to reaching human trials with a PrP-lowering ASO, we are still waiting just like you to see when those trials will launch.

D.T. Max, the writer behind that first New Yorker article about Eric and I, was the first person to say to me of our quest, “You’re running a marathon, not a sprint.” It’s an analogy that has served me well over the years, and also one I poke at in my head from time to time. There are days when we’re more like two people running flat out with no sense at all of how far there is to go, because no one can tell us. There are days when what we thought was just a marathon turns out to be one of those 100 mile high-altitude trail races where all you eat is pouches of goo.

I don’t care for the goo. But when I’m frustrated by the path directly head, I am working on training myself to lift my gaze and look around. These days some of my best sources of optimism are the other people running their own kindred races — here at Broad, here in Kendall Square, and all over the world. Breakthroughs are happening — and they matter for our quest, in ways both foreseeable and less so.

In the very next lane over, tofersen, Ionis’s ASO for SOD1 ALS, just received Accelerated Approval from the FDA. Eric’s blog post on this subject is aptly titled “Tofersen is now the closest thing so far,” in recognition of the close sisterhood between this drug development story and the one we are living. SOD1 ALS, like prion disease, follows a rapid degenerative course. The patients are adults, and the goal of the ASO is to lower the amount of the single disease-causing protein in the central nervous system following drug delivery into the CSF. Provisional approval means that this drug will now be available to patients — making it the new closest precedent we have for a PrP-lowering therapy for prion disease.

Also earlier this year, lecanamab, an antibody treatment that binds amyloid beta fibrils, was granted FDA approval for patients early in the course of Alzheimer’s disease. Based on its Phase 3 trial results, lecanemab appears to be the first disease-modifying therapy for Alzheimer’s to demonstrate a slowing of cognitive decline. An siRNA therapy with a new chemical structure to aid brain delivery showed promising results in a first-in-human safety trial, lowering CSF levels of the causal protein in genetic Alzheimer’s disease. Meanwhile, CRISPR gene therapies, which ambitiously seek to make a one one-time, lifelong alteration to disease-causing genes, have undergone a profound transition. Whereas they were first used on cells outside the body that could be removed and reintroduced, now they are being directly in the human body. Early successes in relatively easier-to-reach tissues such as the liver and the eye are helping to inspire investment in delivery methods for more difficult tissues — even the brain. Week before last, at the annual meeting of the American Society of Cell and Gene Therapy in L.A., multiple scientists from different acadmic and biotech settings presented new viral and non-viral delivery tools for the brain, and in stiking contrast to previous years, most of these data were from monkeys, not mice. While not every vector will survive the leap from monkeys to humans, it’s a smaller leap than that from rodents, and the sheer cost and complexity of monkey studies reflects a level of investment and optimism that I haven’t seen from this crowd before.

Nothing in those last two paragraphs is about prion disease, exactly. The leap of faith here is the belief that in this small world that sits at the intersection of biotech, neurology and rare disease, our fates are never fully independent. There is a feeling here of boats rising: of technological and regulatory precedent, tools with cross-disease application, spillover and good advice. In concrete and meaningful ways, we’re running together.

I’ve said this before, and I stand by it: in some ways, the closer we get to a drug, the harder our mission becomes. As we work to square the richness of the current biotechnological arbor with the nitty gritty, unworthy-feeling obstacles that clutter our days and our inboxes, my optimism and frustration grow ever more tightly braided together. It’s a master class in “both/and” thinking, and frankly, it’s exhausting. As Daruka said to recently as she reclined the tub, gazing at the ceiling, “I do not like my complicated feelings so much. I like my easy feelings.”

And speaking of Daruka, here’s another nugget of bathtub wisdom from her marvelous, almost-six-year-old mind:

Daruka: I wish I was really famous for something.
Me: Why do you want to be famous?
Daruka: I want everyone to know about me.
Me: Why do you want everyone to know about you?
Daruka: Because I’m a really awesome person. And I know things other people don’t know. Like how you don’t have to compete. I know about that… And how you shouldn’t spend all your money on one thing. And how if someone is mean to you, you shouldn’t reflect it back. If they hit you, don’t hit them back. Just be calm. And then tell. And they will fix it. Or don’t tell, and fix it yourself.

Key takeaways for our lab:

Celebrate others’ progress! May all boats rise.
Diversify our bets and keep our eyes open.
Don’t hit people.

She’s not a bad executive coach. Maybe I should issue her a tooth fairy-mediated raise.

Meanwhile Kavari, at three, is growing into a gentler, more sing-songily verbal version of the kid we’ve known, but retains an impishness all his own. If I were to derive life advice from his recent antics, it would probably be, “Pretending to choke is a great way to get attention! It’s hilarious and there is no down side.”

I sometimes wonder if it would be as clear to me, absent our life-or-death quest, that every day with them is a gift. Even when they’re pulling maddening stunts like that.

Thank you, as always, for being with us on this journey.

Sonia and Eric

Another year of progress, in all its complexity

Tue, 29 Nov 2022 12:01:00 +0000

After the incredible generosity you all showed during our ambitious (and successful!) mid-year fundraiser, we’re blessed to yet again have a donor stepping forward to sponsor a match. Donations to Prion Alliance will be matched 1:1 up to $10,000 through the end of December. Donations can be made through Paypal or via check mailed to Prion Alliance, PO Box 391953, Cambridge, MA 02139. Thank you for your continuing support!

Our goal this year was to grow, and grow we did! In total the Vallabh/Minikel lab is now up to a headcount of eight, and the corresponding leap in our lab’s productivity has been breathtaking. Alongside Eric and I the team now includes Meredith, Juliana, Taylor, Vanessa, Ethan, and Raja; more on everyone here. We are privileged to lead a team of such thoughtful and committed scientists. Meanwhile the Broad Institute, and larger Boston/Cambridge scientific community, continue to be a scientific dream home for our mission.

At the same time, the broader world of drug development continues to reveal new complexities. After Ionis previously projected first-in-human dosing of a PrP-lowering ASO in 2022, we are closing out the year without this milestone having occurred. To the best of our knowledge the program continues to progress, but behind schedule. Like everyone else, Eric and I are awaiting updates. We have championed this program long and hard, and it’s disappointing to watch its timeline serially recede into the future. Personally, this year I have come to understand in a deeper way that after years of questing at the level of molecules, now we are questing at the level of human systems.

When we launched this quest more than a decade ago, we knew that biology was complex. We knew that in the man vs. nature matchup that our quest would entail, the complexity of the disease might foil us. I won’t go so far as to say that we’ve put that concern to rest — the biology can always still surprise and confound us. But in PrP lowering we now have in hand a therapeutic hypothesis stronger and better-supported than we could have possibly hoped at the outset. And yet: the road to test this hard-won therapeutic hypothesis in humans is still incredibly long. The onerous finalization of clinical protocols, the administrative onboarding of clinical trial sites, the initiation of the first experiment, the enrollment of sites and of patients, the locking up of data from the first experiment until pre-specified analysis points, samples sitting in queues waiting for analysis… all this just to glimpse the very first data, of much, from the very first study, potentially of many, before a drug might someday officially be deemed effective. Before it might be approved and made broadly available to patients. And that’s only if everything goes right.

If this system feels at times like a maze, it is ironically a maze that shares our goal. A maze built with the noble goal of promoting human health, developing drugs and saving lives. Yet the maze presents us with a new failure mode we must guard against: winning on the playing field of molecules, only to run out of time on the playing field of human systems.

This call to action for ourselves is not to fault any individual or role. In fact, it has been a unique privilege of our quest to interact with such thoughtful and passionate people in all sectors: academic, industry, regulatory. As individuals, they feel our urgency. But as in any complex human undertaking, sometimes institutions struggle to be the sum of their individuals. The intent of the thing, the initial spark, becomes harder and harder to detect among the scripted patterns of behavior and communication, the deference to habit and form. That lives are involved can make us perversely more conservative, more likely to ward against missteps by looking to the past, even if its precedents are unworthy of our vision.

In September, I had the tremendous honor of interviewing former President Obama onstage at the Illumina Genomics Forum in San Diego. I got to ask him about some of these very issues. About creaky systems. About hope. Above all, for me it was a much-needed reminder that patience is a practice, not a trait. That change is incremental and that if we wish for the honor of serving as its chaperones, we must make ourselves ever more efficient engines for the conversion of frustration into forward momentum. That the work to solve one meaningful problem, if you care enough, will always unpack itself to reveal messy context and system-wide failures of imagination, all of which are now also your problem. That we must be constantly vigilant, vocal, and feisty; we must be, to a judicious degree and at the right moments, trouble.

While San Diego certainly stands out in the lineup, this year has been rich in opportunities to voice our twin messages of hard-earned hope and painful urgency. Eric and I spoke at academic conferences and seminars, at clinical Grand Rounds and in a number of local fora. We had a chance to participate in Broad’s “Science for All Seasons” talk series, which is geared towards the science-inclined public; you can see our recorded talk here. We circled back on our first ever prion research project (!), writing up the outcome of our 2013 crowdfunded campaign to test the small molecule anle138b in mouse models of genetic prion disease; you can read Eric’s reflections on what this work taught us, how it kickstarted us forward, and what we’ve learned in the intervening years. (A big shout out to all of you who remember the grassroots hustle of those early days, and have been with us ever since!) We published a hard look at preventive clinical trials in neurodegenerative disease, finding evidence of missed opportunities: overwhelmingly, to this day, trials focus only on already-sick patients, and a surprising number are simply retesting existing drugs in very slightly different ways, rather than testing new drugs with the hope of radical impact. I had the opportunity to work closely with acclaimed genetic counselor Jill Goldman to update the genetic counseling guidelines for prion disease, a project about which I spoke at the National Society of Genetic Counselors’ annual conference in November. This was a personally powerful undertaking for me — a chance to revisit my own counseling and testing experience, touch in with the residual disappointment I was carrying, and find that I was ready to set it down. My cousin Usha recently shared a beautiful quote with me: “Forgiveness is giving up hope for a better past.” In parting with this hope I found myself ready to focus instead on helping to pave a better road for those who follow. You can read more about this experience here.

On a lighter note, recently Eric and I were recently interviewed by NPR’s Short Wave podcast and were featured in episodes 2 & 3 of their series on prions (also available on Spotify and Apple Podcasts). It was a wide-ranging chance to talk science and mission but also personal journey and family life, right down to our breakfast routine.

Well-powered by beautiful breakfasts, at home the kids continue to thrive. Daruka, now five, has dived headlong into kindergarten without a backward glance, and has fast earned herself a reputation as that kid whose hand is always in the air. A new maternal undertow tugs as she inherits my ancient crowns: nature nerd, bookworm, wannabe Mario Kart addict reigned in only by her parents’ elaborate rationing, kindergartener who wields big words out of context then watches slyly to see if she’s passing. Kavari, heartbroken to be left behind in toddler-land, is hellbent on finding a warp that will speed him across their 2.5 year age gap and into the realm of the big kids. But he still hasn’t mastered his tiny-man temper, which sometimes sends him spinning in circles, small fists akimbo, in teary, desperate search of something to pummel to make it all right. In this state he is apt to inform Eric and I, with great severity, that we are “bad guys.”

Over time, we’ll paint a picture for the kids of the complexity that all of us are up against: a world where everything isn’t all right, but where there are no bad guys, not really. Think of a Mario Kart grand prix, we’ll tell them. Every driver sees the same track, just a little differently. In our little view box, each of us is protagonist — even Waluigi and Dry Bones Bowser. Sure, taken as whole we’re a bit of a ragtag crew, but we’re not so unalike, all just fumbling to make the most out of our parameters and constraints as we charge, mostly together, down the track.

Thank you for being with us in this race.

Guidance on genetic counseling in prion disease

Thu, 28 Jul 2022 12:01:00 +0000

In the fall of 2011, Eric and I went through the harrowing process of getting predictive genetic testing. We had just learned the true cause of my mom’s death the year before, and come to understand that I was at 50/50 risk of having inherited her disease-causing mutation. We knew we wanted to move forward out of the sickening limbo this news had thrown us into. The strain and distraction of constantly wondering was not sustainable for us. The available path forward was testing. Not a comfortable prospect, but for us, the best of our bad options: a way to at least resolve the limbo, one way or the other. Quickly, we hoped.

After all we had been through losing my mom and learning about my risk, it would be lovely to imagine that the testing process might be smooth and swift. It wasn’t. We needed a medical professional to draw my blood, order the test, and receive and share the results. But as we talked to doctors about helping with this, a requirement emerged that we see a genetic counselor first, perhaps multiple times. Was this law, best practice, or physician uneasiness in the face of an unfamiliar rare disease? Some combination of all three? It wasn’t clear. I felt that at one of the most vulnerable moments of our life, we were being given the runaround. Many genetic counselors we contacted refused us, often citing lack of expertise in the disease. Every week that passed was another week of waking up in limbo, feeling tortured by my lack of access to a piece of information encoded in every cell of my own body.

In the end, we saw multiple genetic counselors. I don’t want to throw anyone under the bus here. Blame isn’t a useful frame for what was, in my final accounting, a system failure. But I will say that I came out of the experience feeling that the process had not served us.

I wish I could say that I did some deep breathing, processed my negativity and came to a gracious inner truce with the genetic counseling industry, built on empathy for the flux the field is in and the tremendous difficulty of the job. But in truth, it took me years to move past my sense of having been wronged. Years in which, through our work, I came to appreciate the wide, dynamic universe of rare genetic diseases, and the difficulty of understanding the shifting landscape of each. Years in which I met many other families impacted by genetic prion disease and heard many stories about their counseling and testing experiences. Some received no counseling at all, which led to its own confusion and distress. Some received inaccurate information. Some received accurate information but were left feeling abandoned with terrible news, without any resources or support to help them process it. Virtually all, no matter how they felt or had approached their prion disease risk, had family members who were feeling or doing exactly the opposite.

Over those years I began to accept invitations to speak to genetic counseling affinity groups, training programs, and societies. And I began to open my heart to the good these counselors and counselors in training wanted to be able to do for my community and so many others. The counselors I met were enthusiastic, earnest, and knowledgeable, and had chosen an emotionally challenging career path in the hope of being of service and support. These encounters, more than anything, helped me identify the opportunity in my own experience to help fill a need. Genetic prion disease is rare, and I can’t blame individual genetic counselors for not encountering it routinely in their practice. But we on the research side can collaborate into the genetic counseling field to make sure that current information on prion disease risk is synthesized with current counseling best practices, updated frequently, communicated clearly, and made available so that any practitioner with the right general background can efficiently tailor their expertise to serve a prion disease patient or family. We can arm them, too, with information about how the field is changing, on how to get involved, and on who to contact for support.

To this end, Jill Goldman and I have just published a piece entitled “Genetic counseling for prion disease: updates and best practices” in Genetics in Medicine. The piece is open access and available to anyone who needs it. I’m proud to have had the opportunity to partner with Jill on this effort — in addition to being a deeply experienced genetic counselor in the realm of adult-onset neurodegenerative disease, she is one of the few genetic counselors I’m aware of with a specific expertise in genetic prion disease.

In the article, we overview what is currently understood about the risk associated with different prion protein variants, including penetrance (the likelihood of developing the disease if you carry the mutation), age of onset, duration of disease, disease presentation, and variability in all of the above. We address questions that may arise in counseling a currently symptomatic patient and an at-risk individual, and questions that may arise with family, whether in a session or separately. We provide information on testing through the National Prion Disease Pathology Surveillance Center, on seeking support from the CJD Foundation, on joining PrionRegistry,org and on accessing more information on the science of prion disease through Prion Alliance and cureffi.org. Finally, we speak to the prospect of clinical trials and the transformative value of participating in research — especially in a rare disease — if one is so inclined.

We are blessed that the landscape of prion disease is changing rapidly — we are gathering more data all the time and, most importantly, we are making progress towards new prospective therapies. So, it is actually good news that an article like this one won’t stay current for very long — it will and should be superseded by a new update every few years. With that said, for now, I hope this tool will fill a need. I hope it will allow more genetic counselors to feel confident supporting the families in our community, across the spectrum of preference — from those averse to testing to those who are uncertain to those who, like me, know they want to test and feel tortured by every delay. I also hope it will help them convey the nuance of our current moment. Prion disease remains untreatable today — but we have more hope of a therapy in our lifetimes than we ever have. Despite the rarity of prion disease, we have strong diagnostic tools, robust patient support groups, and a level of organization that will facilitate future clinical trials. We have new reason to believe that engaging with genetic risk early may eventually open up the possibility of preventing or delaying disease, extending healthy life. This is a lot to have — and this list is growing in real time.

No one wants to be in the position of being counseled on prion disease. I certainly didn’t want to be. And I can’t rewrite the way those terrible months at the end of 2011 played out for me. But I hope that in lieu of being able to change the past, we can seize what opportunities we have to change the present — by making sure people who find themselves at that same vulnerable crossroads are given clear information, support, and hope, no matter their test result.

And meanwhile, of course, there’s the important work of changing the future, by doing everything we can to hasten the day when a positive test result comes with a treatment plan, and a prospect for a long and healthy life.

Prion Alliance mid-year update 2022

Tue, 07 Jun 2022 12:01:00 +0000

Dear friends and supporters,

It’s a busy and ambitious time in our lab and we are grateful as always for your support. A group of donors have generously offered to match your donation 1:1 up to $100,000 through the end of June, so if you can, please chip in to support our research at prionalliance.org/donate or mail a check to Prion Alliance, PO Box 391953, Cambridge, MA 02139.

Our number of projects is forever multiplying, and so, fighting hard against the tough hiring market, we’ve been recruiting aggressively and have new staff starting this summer who will collectively double the size of our lab. This amount of growth is ambitious for us and we need your help to make it work financially — hence the June donation matching campaign. But we must, because there is just always so much science to do. With several new animal models, ever more complex therapeutic studies, myriad biomarker assays, and loads of preliminary findings to follow up on, growing the lab has become an imperative, and it suddenly feels a long time ago when it was just the two of us as PhD students, fighting to move a couple of projects over the finish line.

Adding to the urgency of all our work is the prospect that clinical trials could be just around the corner. Ionis Pharmaceuticals has not updated the last official timeline it gave to the patient community: that first-in-human trials might begin by late 2022. Or course, various obstacles biological, regulatory, and otherwise could always still crop up at any time, so we can’t be complacent, but we should also be prepared for the possibility that, after all these years of preparation, human dosing could begin this year.

News on ASOs for other neurological indications continues to trickle in. After very disappointing results in 2021, Roche may be reviving its Huntington’s disease ASO after all. In longer-term follow-up, an ASO for one form of ALS looks possibly more promising than initially thought. But meanwhile, an ASO for a different form of ALS failed miserably in a Phase I trial this spring. Overall, the track record of ASO drugs for the brain that is emerging is a complicated picture. Many different things need to go right in order for a drug to work. Therefore, when drugs fail, it’s not easy to know if the issues are specific to the patient population, the disease, the drug, or the class of drugs. The recent failures don’t make us lose hope that an ASO for prion disease will be successful, but they do remind us that a clinical trial is, after all, still an experiment — not a cure — and we should be prepared for any result. After years racing to this point, the first human trial feels like it should be a finish line. But the truth is, it’s just a starting line.

Thank you for being with us in this journey. We hear every day from people who are losing loved ones, and we weep for those for whom all this progress has not come fast enough. Whatever the news brings each day, when we fix our eyes on the longer term, we continue to feel filled with optimism.

all our best,

Eric & Sonia