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