Ten years ago today, Eric and I received my genetic test report, an event that changed our lives completely, and set in motion our quest to cure prion disease. In honor of which: donations to Prion Alliance will be matched 1:1 up to $60,000 through the end of December. As always, you can donate through Paypal, or mail us a check at Prion Alliance, PO Box 391953, Cambridge, MA 02139. And also as always: thank you! Note: the match will also be retroactive from December 1, so don’t worry if you already donated this month.
If not quite as surprising as 2020, this has nevertheless been a year of ongoing challenge for virtually all of us, and we hope that this note finds you healthy and well, with room in your heart for optimism about what 2022 may bring.
For us, 2021 was a bit of a mixed bag, though perhaps it’s hard for an entire year in any human enterprise to be otherwise. Following the pivot towards a new lead drug candidate that we shared mid-year, our collaboration with Ionis Pharmaceuticals continues to move toward the clinic, with hope of first-in-human dosing of an ASO in 2022. In anticipation of soon joining their ranks, we are watching other clinical ASO programs for neurodegenerative diseases closely. Two important trials read out this year, one in Huntington’s disease and one in ALS. For a detailed analysis, you can read Eric’s cureffi blog posts on both trials, here and here. In a nutshell, the results of the Huntington’s trial were disappointing, while the ALS trial showed positive results on some fronts without being quite a home run. In both cases, there is much still to learn — clinical trials amass an unbelievable amount of data, and analysing it fully is a major, years-long undertaking. We’re fortunate to be in a position to benefit from the learnings from these programs, and I feel a great debt to the the patients and families who volunteered for these studies.
Among other takeaways, the more I learn the more stunned I am by how many stars need to align for a clinical trial to meet its goal, even if both the therapeutic technology being employed, and the therapeutic hypothesis being tested show reasonable promise. The devil is in the absolutely endless, branching tree of details: how many people to treat, how often, at what dose, and when in their disease course; how similar the treated patients need to be, on which dimensions, and how long they should be followed; what should be measured to assess if the drug is working, by whom, using which tools, when and how often; how these outcomes should be ranked in importance; what, at the end of the day, among all available options, the go/no-go decision should rest on. The relationship between these completed trials, and those we hope will soon begin in prion disease is complicated, but one thing we can count on is having to grapple, in the context of our disease, with all of these same sticky questions, and many more.
I once had a law professor who quit his job at what was arguably the most prestigious law firm in the US, the day he made partner. By way of explanation, he quoted an old saying: “Making partner is like winning a pie-eating contest where the prize is more pie.”
We’ve come this far to develop a PrP-lowering therapy. We’ve completed a possibly record number of preclinical studies, with more underway. We’ve done biomarker studies, developed assays, followed a natural history cohort for four years and counting, helped launch a patient registry, met with FDA. We’ve helped usher a drug to the brink of trials. This is more progress than we could have hoped for when we first launched our quest ten years ago. And now it’s time to eat more pie.
2021 has been a big year for the Vallabh/Minikel lab. This summer, we formally moved to a beautiful new lab space within the Broad Institute, nested in the Stanley Center for Psychiatic Research. In addition to spanking new facilites, here we neighbor a number of other labs working on brain diseases, with exciting opportunities for cross-pollination. In October, Broad met it’s goal of becoming a 100% COVID vaccinated workplace, with the happy consequence that our lab is now able to safely be on site, full time. We hired two new lab members this year — you can meet the team here — and just opened a search for a new post-doc. If you know a good candidate, please send them our way!
We also brought two new animal models into our lab: in addition to mice, which we’ve worked with for years, we now have rat and hamster models of prion disease up and running. The immediate goal is to use these new models to demonstrate that lowering PrP is beneficial across a variety of paradigms — it’s not just a mouse thing. But in the longer run, these models may have much more to teach us. Among other advantages, their larger size lends itself to easier collection of blood and spinal fluid, which will help us to connect the dots between biomarkers in prion animal models and in human patients. And speaking of biomarkers, following a COVID hiatus, our MGH clinical study of healthy genetic prion disease mutation carriers, at-risk individuals and controls has fully reopened as of this fall, and is now in the exciting position of recruiting new participants — more info here if you are interested! The more we can expand this cohort, both in size and over time, the more we will learn about how to do trials in healthy people at risk — and, once useful drugs exist, how best to leverage those drugs to keep carriers healthy for the long term. Thank you so much to those of you who have contributed to this study in some way.
At home, our kids continue to remind us that progress comes in many forms. Daruka, at four a prolific maker of treasure maps and potions, is nearing a breakthrough in how to add numbers larger than the number of fingers she has. The breakthrough involves toes. She wears a full-body Spiderman suit to school at least once a week and is stern about how we address her. “You can call me Spiderman,” she tells me. “Or,” she concedes, “you can call me my sweet, sweet Spiderman.” Kavari, at nearly two, shy with words until he suddenly wasn’t, has recently unlocked the ability to cheerlead his own whimsical avalanche of vocabulary. New words are followed by a “yay!” of self-approval and a solemn, lengthy round of self-applause.
When I think back on the arc of our quest to date, there’s an eerie parallel with the experience of parenting two young children through the past two years of the COVID pandemic. Namely, if someone had sat me down ahead of time and laid out just how hard it was going be, I’m not sure if I would have had the stomach to take it on — and so, thank goodness I didn’t know. There’s something to be said for our inability to peer even a foot into the future. We cast our dice, bound our lives to these two impossible callings that fill our hearts and days, and I wouldn’t have it any other way.
Thank you for everything. Here’s wishing for the best in 2022.
Sonia and Eric