CRISPR Stops Rare Genetic Disease In New Human Trial
When the gene-editing technique CRISPR first came on the scene in 2012, researchers were excited by the potential the technology offered for editing out defects in genetic code, and curing genetic diseases. The researchers behind the technique, Jennifer Doudna and Emmanuelle Charpentier, won a 2020 Nobel Prize.
In one of the first clinical applications of the technique, last month researchers reported in the New England Journal of Medicine that CRISPR had stopped a genetic disease called amyloidosis, which occurs when an abnormal protein accumulates in your organs. They’re not the only group moving toward using CRISPR on humans; recently, the FDA approved a human clinical trial that will use the technique to edit genes responsible for sickle cell disease.
Fyodor Urnov, a professor in the department of molecular and cell biology at the University of California at Berkeley and the director of the Innovative Genomics Institute, joins Ira to discuss the clinical trials, as well as what other therapeutic targets for CRISPR-based gene editing lie on the horizon.
Invest in quality science journalism by making a donation to Science Friday.
Fyodor Urnov is a professor in the Department of Molecular & Cell Biology and director of the Innovative Genomics Institute at the University of California, Berkeley in Berkeley, California.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. When the gene-editing technique CRISPR first came on the scene, researchers were excited by the potential CRISPR offered for editing out defects in our genetic code and therefore curing genetic diseases. The researchers behind the technique, Jennifer Doudna and Emmanuelle Charpentier, won a 2020 Nobel Prize. But the promise has been slow to yield results until now.
Last month, researchers reported, in the New England Journal of Medicine, that CRISPR had stopped a genetic disease, amyloidosis, in its tracks. And recently the FDA approved a clinical trial that would use the technique to edit genes responsible for a sickle cell disease. Joining me now to talk about those and other therapeutic uses of CRISPR, on the horizon, is Fyodor Urnov. He’s a professor in the Department of Molecular and Cell Biology at UC Berkeley and director of the Innovative Genomics Institute there. Welcome to Science Friday.
FYODOR URNOV: Thank you for having me.
IRA FLATOW: Did I get that study correct, published in the Journal?
FYODOR URNOV: You did, except I would have added emoji of excitement and, you know, champagne bottles.
IRA FLATOW: [LAUGHS] Well tell us about what happened, how it was done, and why people are so excited by it?
FYODOR URNOV: It is literally a dream come true. We’ve known that diseases can be genetic for well over a century. We’ve known about sickle cell disease and its genetic basis for 70 years plus. We first read human genes in the 1970s. And we first read all of human genes, in the DNA of just a few people, in the early 2000s. CRISPR is the equivalent of flying to the stars if we were astronomers. We’re no longer now limited to cataloging the stars/genes. We can fly to them. We can touch them. And we can change them.
All of this was a promise. And, as you mentioned, Jennifer and Emanuelle’s landmark 2012 Nobel Prize-winning paper– it’s remarkable that it’s only been 10 years, progress has been so fast– proposed the notion that we would use CRISPR to change DNA to treat disease. And a large community of folks– let’s just be clear, this is a proverbial village raising this child, scientists, physicians, regulators, ethicists working all over the globe. But there we have it.
We have our first poster humans who have been gene-edited. They walk our planet. And fortunately they seem to be well. So nothing bad happened. The first rule of medicine, do no harm. And, even more fortunately, they are thriving. And we have every reason to believe that having gene-edited them will help them.
IRA FLATOW: Tell me about the experiment. Walk me through what actually happened.
FYODOR URNOV: It may surprise you that what actually happened in the most recent work with the amyloidosis was very similar to what happens when you get vaccinated for SARS-CoV-2. And folks who have had the vaccine made by Pfizer or Moderna have now learned rather convoluted things like lipid nanoparticle or messenger RNA. It’s kind of amazing to me that 2020 has gotten us to a point where most folks know what those acronyms mean.
With CRISPR, that same messenger RNA encodes a protein which does not have a poetic enough name. Its name is very bland. It’s called Cas9. It’s Mother Nature’s device, which, of course, people have repurposed as guided by Jennifer’s and Emanuelle’s discovery, that can seek out a stretch of genetic code and tell Mother Nature to repair it. So, in the case of the most recent experiment with TTR amyloidosis, messenger RNA encoding this wonder protein, Cas9, along with a wonderfully named guide, a separate short snippet of RNA that tells Cas9 which gene to change, was injected into six people.
It’s not just naked RNA. Just like with a SARS-CoV-2 vaccine, they’re encompassed in a protective layer called the lipid nanoparticle. And it routes itself through the bloodstream into the liver. And then the messenger RNA makes Cas9 protein. Cas9 wakes up inside the cell of the liver, takes this little guy that it has, goes into the nucleus of the cell, finds the gene which causes the disease, and gets rid of it. Now that happens at the cellular level. And the reason we’re all frankly waking up with a smile on our face and a sense of strong motivation every morning is it’s all well and good to do this in the lab or in mice or monkeys, but humans are a different matter.
Full credit to the biotechnology company, Intellia, which did this work. Great, great job. They did this on six human beings. In technical terms, they’re known as subjects. The subjects are doing well. There’s nothing adverse happened to them as best as we can tell. And critically, when physicians who actually did the injection measured some critical biological features of these humans, they’re doing well at the molecular level. And what that means is we have strong hope that this severe disease they’re succumbing to, which damages their nerves, damages their heart, et cetera, is actually going to be reversed.
IRA FLATOW: Now I hear, and I understand your enthusiasm, your joy is palpable. But it is a very small, with equals 6 or something, a very small sample, is it not? Are we a little too excited too soon, or not?
FYODOR URNOV: You raise a key point. These are experimental treatments. And the central goal of our entire community is to do everything we can to focus on safety first. Now a number of groups around the world, both biotechnology, and I mentioned Intellia, there are other companies, and a number of academic groups,
I’ll just mention as a representative example Children’s Boston, St. Jude in Memphis, and here, at UC Berkeley, the Innovative Genomics Institute which Jennifer Doudna founded in partnership with the University of California San Francisco and UCLA, we are developing CRISPR-based methods to treat other diseases, including sickle cell disease. Our number one concern is that we will cause harm. That risk is non-zero. We will never know it’s completely safe until we actually treat human beings.
So safety first. We’re taking it slow. So, for example, the clinical trial that we’re honored to have been supported by the California Institute for Regenerative Medicine to do, this is a joint effort between UC Berkeley, IGI, UCSF, and UCLA, the vision is to treat nine people but do that over three years. And so why so slow? Well you treat one person, and you see how it goes. And if they’re doing well, then you treat another person.
So this staged dosing, here’s a technical term, staged dosing, which means one person at a time and walk before you run, precisely addresses the question you raised about not getting too excited too soon. It’s early days.
IRA FLATOW: And tell us about your time frame for that sickle cell study because people, they’re going to hear this. They’re going to hear this. They’re going to say, I want this. You know how this works. People get very hopeful.
FYODOR URNOV: Here’s, in practical terms, what’s going to happen. Assuming things track to plan, UCSF, which is where the clinical trial will happen, Mark Walters is our principal investigator, we’re hopeful to treat the first patient this year. But I want to paint a slightly bigger picture which is the IGI is not alone. And that’s actually really important. We are not the patient’s only sort of hope.
And number of biotechnology companies, and I’m might just actually going to list them all because I think it’s important that your audience is aware of who else is doing this, Sangamo, CRISPR Therapeutics, Editas Medicine, Intellia Therapeutics, and Graphite Bio all have open clinical efforts for sickle cell disease in addition to us at the IGI, and UCSF, and UCLA.
All in, we are expecting that, over the next three to five years, this combined effort, assuming things go to plan and nothing goes awry which we always wake up with both equal parts excitement and concern about safety, assuming things go to plan, we are hopeful as a community to treat, I’m going to go– give a relatively low number but bear with me, maybe 100, 200 folks with sickle in the United States over the next couple of years.
But the really important point, Ira, that I think I want to communicate is experience shows that, when a treatment such as what we’re seeing with CRISPR has an effect as powerful as it appears to have, then, in contrast to other diseases for example cardiovascular disease or neurodegenerative disease where the Food and Drug Administration sets a standard that you have to study thousands of individuals over many years, experience shows that to do a clinical trial that convinces the Food and Drug Administration that this is a medicine that should be approved, those trials are relatively small in size and could be as few as 20, 30, 40 individuals per individual approach, let’s just be clear.
And that means that, assuming things track to plan, within a few relatively short years, we should expect, again fingers crossed, multiple approved genomic therapies, such as CRISPR, for sickle cell disease in the United States. And at that point, that means that physicians, in America, will be able to quite literally prescribe a CRISPR gene edit for a human being with sickle. Now I would like to take an important detour into the issue of health justice.
These genomic therapies, when they are approved, cost millions of dollars per person. There is a genomic therapy for spinal muscular atrophy. It’s $2 million. There’s a therapy for blindness. It’s $850,000. We, as a nation, have a responsibility to ensure equitable care for our fellow Americans. A good fraction of folks with sickle, in the United States, are of African-American ancestry, so this is a community that oftentimes is socioeconomically disadvantaged.
Here in California, we have– I have 10,000 of my fellow Californians with sickle. And less than 20% have private health insurance. They can’t afford a $2 million per person cure. So, now switching to the realm of academic medicine, a vision for the Innovative Genomics Institute is health justice and health equity. It’s deeply moving to me to work with Jennifer Doudna because she set a mandate for our institute. We have to develop CRISPR cures that would be equitable. And I don’t want to position this as a zero-sum game, academia versus industry.
But I do want to say that we, as a community, as a nation, have a responsibility to make sure that these remarkable technological innovations are equitably administered. And I cannot think of a better example than, to showcase how good we are as a nation, is than in building a health-just distribution of CRISPR and other genomic therapies for our fellow Americans, many of whom are socioeconomically disadvantaged.
IRA FLATOW: Talking CRISPR gene editing with Fyodor Urnov. He’s a professor in the Department of Molecular and Cell Biology at the University of California at Berkeley, director of the Innovative Genomics Institute there. This is Science Friday from WNYC Studios. Are there other sorts of conditions or diseases that would yield itself to CRISPR therapy? I’m sure there are plenty, correct?
FYODOR URNOV: You know, I’m wondering if we can schedule Science Saturday and Science Sunday so I could do full justice to what– So first let me be clear. There is no low hanging fruit. These are experimental therapies. And these are hard. I’m going to showcase the things that are the low-hanging of the high-hanging fruit. The first one is other genetic diseases of the blood. And this is because we can take blood STEM cells out of a person, CRISPR them, quality control them, and put them back in.
And a major need are the so-called rare genetic diseases of the blood like immune deficiencies or disorders of the immune system. I put quotation marks around the word “rare.” They’re rare individually. There’s maybe, let’s say, 50 people in America with disease number four. But in aggregate, they’re actually quite abundant. And here, health justice is yet again an issue because it’s one thing for a biotechnology company to pursue sickle cell disease. They have 100,000 patients ready to receive their medicine if they succeed. But who is going to spend time and money building a medicine for which there’s 20 patients.
So again, I’m honored to be partnered with UCSF and the Gladstone as part of the Innovative Genomics Institute to address that question. How do we develop CRISPR technologies where we can equitably and affordably CRISPR treat somebody who is the proverbial n equals 1? There’s only one person with that rare genetic disease or maybe five. How do we innovate in the CRISPR space where we can treat that person? So that’s area number one. Genetic diseases of the blood, immune system, absolutely goal firmly in our sights.
Now stepping away from blood disorders, I think an area of everyone’s deep scientific passion are disorders of neurodegeneration. We are actively working, in partnership with UCSF here at the IGI, to build CRISPR approaches for neurodegenerative disease. And I want to be very clear to not give folks false hope. But I just want to say that we, as an institute in partnership with UCSF, are actively working on this as are many others.
Another area, which I can actually give you a specific in terms of hope coming in focus actually, is heart disease. Cardiovascular disease is a major killer and continues to be. And as tasty as butter is, it’s on balance not very good for you. Olive oil is better, but we can’t change people’s habits overnight. So what if we could CRISPR someone in a way where they would be genetically protected against heart disease? And that’s actually not science fiction.
I want to highlight work from a biotech company called Verve, V-E-R-V-E. And they’re doing precisely that. They’re working on a next-generation form of CRISPR, something called base editing, which was invented by David Liu at the Broad. And they are working to put a CRISPR base editor into a person so that, just like Intelia did for amyloidosis, it would go to the liver. But instead of going after a gene that causes that disease, it would tweak a different gene that we know, from all sorts of experimentation, would give a person, we hope, a lifetime of protection from heart attack.
This is actual late-stage preclinical reality. We are all, as a field, hopeful that verve will go into the clinic next year. And again, folks will start sending emails going, when– where do I sign up for some CRISPR protection against cardiovascular disease? These things take time. I would anticipate that these clinical trials will take four to five years to play out. But there’s solid scientific foundation for this. There’s clear proof of concept, for example, from the work of Intellia. And enthusiasm is, as we discussed earlier, healthily married with concern about safety.
But frankly, Ira, let me just say this. We have irreversibly stepped into an age of genetically engineering human beings to treat their disease. There are CRISPR humans among us. Their numbers will only rise. And there will be CRISPR for blood disease, for rare disease, for neurodegeneration, cardiovascular. I also want to highlight cancer, some beautiful work from the University of Pennsylvania led by Carl June and many others, including biotech companies. Watch this space please. The next five years will be quite a ride.
IRA FLATOW: Dr. Urnov, fascinating stuff. We have run out of time. I want to thank you for taking time to be with us today.
FYODOR URNOV: Ira, what an honor frankly to speak with you. I’m a lifetime fan, and I can’t believe– I’m pinching myself– I found myself speaking with you on air.
IRA FLATOW: Oh thank you. You’re too kind. I’d like to thank you for the kind of work you’re doing. And good luck. We’ll be keeping close attention, paying close attention to it
FYODOR URNOV: I appreciate it.
IRA FLATOW: Fyodor Urnov is a professor in the Department of Molecular and Cell Biology UC Berkeley, director of the Innovative Genomics Institute there. And we will be watching, as I say, the future of CRISPR technology.