With fewer than 400 progeria patients worldwide, testing a CRISPR cure will be challenging

When Sammy Basso was diagnosed with progeria at 2, it seemed likely that the disease’s hyper-accelerated aging would kill him before he graduated high school.

“There was nothing. Nothing. No cure, of course, no treatments, no information. It was catastrophic,” said Basso, spokesperson for the Progeria Research Foundation, at STAT’s Breakthrough Science Summit on Wednesday. “Nobody could believe that we will be able to arrive at this point. But here we are.”

What he meant was that the last two decades have seen a dramatic surge in scientists’ understanding of progeria. It has brought not only an approved drug for the disease — one that’s helped Basso live to 25 — but also a potential cure, which has so far worked in mice, and for which researchers hope to start clinical trials soon.


Designing a human study for such an ultra-rare and deadly disease poses a challenge, though. With only 400 progeria patients worldwide, there aren’t enough of them for traditional trials — and the disease is so deadly that to give them a placebo is viewed as unethical.

Plus, they don’t have much time. Progeria is a genetic illness that seems to speed up time. A baby will seem healthy at birth, but then, at some point in the next year or so, proves not to be growing at a normal rate, loses fat under the skin, and starts prematurely showing the health problems of old age. On average, patients with untreated progeria live to the age of 14 and a half, their deaths often caused by cardiovascular disease or stroke.


The biology behind this first emerged in 2003. During his medical training nearly 20 years earlier, National Institutes of Health Director Francis Collins had seen a patient with progeria, and when advocates said they were looking for researchers to help, he felt invested and began asking around. “After I tried to get other people interested in working on this to find the cause, I decided, ‘Well I’ve got a lab, and my postdoc’s looking for a project, and so Maria, why don’t you see if you can figure this out?’” Collins said during the panel.

It was a challenge, but she did — with help from many colleagues. (Her name is Maria Eriksson, and she’s now a professor at Sweden’s Karolinska Institute.) “Almost all of the individuals with progeria had a single letter of the genome out of 3 billion that was misspelled,” Collins explained — and that tiny typo was giving rise to a toxic protein that shortens the life spans of cells. “We thought, ‘Gosh, maybe there’s some way — somehow, someday — this could lead to a benefit,’” he said.

The benefit arrived, in a way, because David Liu, vice-chair and core faculty member of the Broad Institute of MIT and Harvard, saw an interview about progeria on TV. That put the disease on his radar screen, and years later, when his lab was working on a more precise way to edit DNA than your run-of-the-mill CRISPR Cas-9 system, his team saw that the technique could change that particular progeria-causing typo.

“It does so not by cutting and messing up the gene as CRISPR as [it] evolved in nature, does,” Liu explained. Rather, it uses CRISPR’s ability as a kind of guide, homing in on the genetic bit that needs to be changed, but instead of slicing into the double helix and potentially screwing up genes, it rearranges the atoms in one letter — known to biologists as a base — so that it becomes a different one. Hence the name base editor.

Working with Collins, Liu found that this editing tool helped patients’ cells in a dish, but also allowed mice with progeria to survive longer — results they published in January 2021.

Now, the researchers are trying to assemble all the data they need to apply for regulatory permission to start a clinical trial. That’s hard for most diseases, but even harder for progeria. “Time is not on our side,” said Leslie Gordon, co-founder and medical director of the Progeria Research Foundation, and professor of pediatrics at Brown University.

“The worst thing that could happen in a clinical trial is you design it so that you don’t really know the answer,” said Gordon, who lost her son Sam to progeria. A traditional study would recruit patients, give some of them the drug, some a placebo, and then compare how they do. But that approach doesn’t work for progeria — and so in trials for the currently approved treatment, researchers compared participant results to data on untreated progeria from past studies. On average, that treatment added two and a half years to patients’ lives.

The trial that the panelists are now working toward has to account for the fact that participants are so few and far between, and may not have long to live. “We’re changing the traditional paradigm of what has to be there in order to run a clinical trial that cannot be there for rare diseases,” said Gordon. “We don’t have 100, 200, 1,000 children. We have to design something where you at least can get a hint, you know, a symbol… We have to design something that works for this population, for these kids.”

It isn’t easy, by any means. The progeria community is one that’s plagued by loss. Every time a patient passes away, Basso said, “it is to lose a brother, a sister.” But he’s also watched his disease go from being unexplained to having a potential cure — a remarkable biological feat: “Every scientific discovery is like a party. It’s a party for these families.”

Source: STAT