RARE Daily

Speeding and Scaling the Development of Genome Editing Therapies

March 7, 2024

Earlier this year the Innovative Genomics Institute and the life sciences tools conglomerate Danaher launched a collaborative center to develop genome-editing therapies for rare and other diseases. The Danaher-IGI Beacon for CRISPR Cures seeks to address hundreds of diseases with a unified research, development, and regulatory approach. Their goal is to create a new model for the development of genomic medicines. We spoke to Fyodor Urnov, IGI’s director of technology and translation and director of the new Beacon center, about the evolution of gene editing technology, the challenges of a platform approach, and how the organization plans to share what it learns.


Daniel Levine: Fyodor, thanks for joining us.

Fyodor Urnov: What a pleasure to be with you.

Daniel Levine: We’re going to talk about CRISPR gene editing, where we are in the evolution of the technology, and a recent agreement between the Innovative Genomics Institute and the diagnostics conglomerate Danaher to create scientific and regulatory frameworks to speed the preclinical testing and clinical development of CRISPR therapies. Before we talk about what IGI is doing with Danaher, though, I thought it’d be useful to orient listeners a bit. I’m sure most people have heard of CRISPR, but what makes it so compelling as a therapeutic approach?

Fyodor Urnov: Let’s look at the clinical track record so far, and to be clear, if you had asked me this question five years ago, I would’ve gone about hypotheticals—we could fix this mutation, we could get rid of this toxic gene. We now have a medicine approved for the two most prevalent genetic diseases on earth, sickle cell disease, and a related disorder, thalassemia, and they’re both CRISPR powered. And in both cases what has happened is folks suffering from one of these two conditions, which are really dire in the United States, the 20,000 or so folks with severe sickle cell disease, their life expectancy is around 40. A person with sickle in Sub-Saharan Africa has a life expectancy of five. So it’s really devastating. So folks like that, and there’s at this point well over a hundred of them that have been treated with this medicine, come to a hospital, they give some of their blood stem cells to the physician, and then those cells get sent to a CRISPR factory. You heard that, right? Literally a place where cells get CRISPR, they get treated in that factory with this amazing molecular device, which goes inside those cells, finds the right gene to tweak and tweaks that gene literally the way you would use a word processor to repair a mistyped word in your document, and then the cells get flown back to where that patient is and get put back in. And amazingly, we have many folks, our fellow Americans and in Europe as well, that have had this done to them and they no longer experience the devastating pain episodes that are a tragic hallmark of this disease. They no longer need blood transfusions.

So, what is CRISPR? CRISPR is a molecular machine. I know that sounds ominous until you figure out what it’s done—that we can program using rules that Jennifer Doudna here at UC Berkeley, in partnership with Emmanuel Charpentier, discovered 11 years ago—how to program it to go and do this gene tweaking. And here we are a mere decade later with an approved medicine. So, you could argue, well, isn’t this one trick pony? Well, no, a biotechnology company called Intellia has taken dozens of folks with a severe disorder in which their liver secretes into their blood really basically a poison, the product of a broken gene. It’s a toxic protein that poisons their muscle, their heart, their nerves, and they inject it into those folks. Again, these are people sick with severe disease. To be very clear, we’re not talking about anything cosmetic here, and inject them with a teaspoon of CRISPR. Literally think of a teaspoon of liquid. You inject it in a syringe into your bloodstream. Just a month later, that toxic protein is basically gone from their blood. You ask me what’s CRISPR? CRISPR is a molecular machine that, based on rules that Jennifer Doudna figured out 10 years ago here on the Berkeley campus, can be reprogrammed to treat a disease of the blood such as sickle cell disease, to treat a disease of muscle, nerve, and heart such as TTR amyloidosis. This is the long form scientific name for that condition Intellia treated. A technology company called Verve is using CRISPR to treat yet a third disorder, cardiovascular disease, and they’ve treated 10 folks in New Zealand with promising results so far. I am looking back at the history of biology and the history of medicine, and we’ve progressed from amazing things like penicillin, which were an accident of nature that was a gift, to targeted molecular therapies like Gleevec for leukemia, to biologics like Enbrel for rheumatoid arthritis, or Keytruda for cancer. I think we are not just at the dawn of the age of repairing DNA to treat disease. I mean, I think the sun has firmly risen over the horizon and is kind of shining at us. It’s benevolent light.

Daniel Levine: I know you’re acutely aware of the global burden of sickle cell disease and the challenges of an ex vivo therapy with a $2.2 million price tag being able to address this need. What’s the potential to drive the cost of producing and manufacturing these therapies where they can be made accessible and developed more quickly to address a wide range of genetic diseases?

Fyodor Urnov: So, in the history of biomedicine, the only technology that has been scaled to planetary level, right, are vaccines. We got rid of smallpox by vaccination, and most recently, and what I think is probably the biggest achievement of the biotech sector to date, companies like Pfizer and Moderna leveraging a lot of innovation from the academic sector have basically manufactured enough SARS-CoV-2 vaccine to basically treat everyone in the world. Has that vaccine been equitably distributed is a separate complicated story, but the sheer fact that a company like Pfizer can make 3 billion doses of SARS-CoV-2 vaccine is astonishing. Why am I telling you this? Because the way that the SARS-CoV-2 vaccine is put together, literally the way it’s cooked, the bits and pieces are the exactly the same bits and pieces that you would need to build a CRISPR. Yep. It’s the same old lipid nanoparticle. I know your audience knows this because of the vaccines. It’s the same messenger RNA that has won this amazing recognition to Katalin Karikó and Drew Weissman across the board. So the fact that the way CRISPR is put into a human being is via a technology that we have already scaled to 3 billion doses is extraordinary to me. Honestly, the challenge is not whether we can make enough CRISPR to treat the world—we can. The question is, are we the kind of species that can ensure that health justice is met? And here, as you allude to, formidable efforts over three decades plus of developing gene therapy have given us curative medicines for spinal muscular atrophy, for blindness, more recently for hemophilia. And the price tags on these make them the most expensive medicines in history. The way I like to frame this is using a quote from a human being living with sickle cell disease. And they were interviewed recently by a leading industry publication and they said, “I have sickle cell disease and I was so excited for this new medicine. And when I looked at the price tag,” and this person continues, this is an exact quote from them, they said, “it felt like I’m a dog and there’s a steak dangled in front of me.” And it’s just so devastating to hear this, that yes, our community of biotechnologists and physician scientists can build a curative medicine that saves a person from a lifetime of pain and disability. And yet there are other features of the way society works that objectively will act as a barrier between those curative medicines in the world. So, our number one goal for the next decade is not just to expand the footprint of CRISPR, but to do so in a way where the technologies are explicitly scalable. In other words, let’s not build a CRISPR medicine which takes five years to manufacture and $20 to $50 million and then take another several years to go through clinical trials, which costs hundreds of millions and ultimately by the time you’re done, the for-profit company that has spent all this money doing that finds itself charging $3 million per dose because they have to recoup the investment. If we stay with that system, I just don’t think that CRISPR will have the impact that it can. We need a fundamentally new way to design CRISPR medicines, test them, manufacture them, and then distribute them. And if that sounds utopian, well it’s utopian emotionally, but not practically, because as you alluded to at the beginning, the Innovative Genomics Institute, which Jennifer founded with the ambitious goal of making sure that CRISPR solutions are available to everyone who needs them, has taken a major step forward, we believe towards that goal. And being joined by Danaher, a leading provider of technology and solutions to biomedicine and in particular the cell and gene therapy sector, where we frankly found kindred spirit folks who agree with us that we have to build CRISPR medicines in a new way and we have to do this scalably. I will have lots more to say about this if there’s time, but the central point to take away from this new partnership is in order for us to jointly expand the benevolent sunlight that is the sunrise of CRISPR, we need to forge creative new partnerships that blur the barriers between academia and industry and recognize that we as a species have a shared public health challenge—300 million folks with one of 5,000 genetic diseases that could be CRISPRed and they’re not under the current system. It’s time to build a new system.

Daniel Levine: Before we talk about what you’re doing with Danaher, though, a lot of the solution that people are thinking about lies in taking a platform approach to doing gene editing. And I know that IGI has been involved in a project that’s funded by the NIH’s Somatic Cell Genome Editing Program to do that. What’s the potential here for a platform approach?

Fyodor Urnov: If you had told me 10 years ago that we would have a way to treat genetic diseases where you could explain how to make the medicine for one disease versus the other to a 7-year-old child, I would’ve politely suggested that you should have some herbal tea. And yet I have successfully explained that how CRISPR medicine design works to my 7-year-old daughter. And she listens to this and goes, wait, that’s it. There’s nothing more to this. I’m a little bit exaggerating of course, but we all remember, everyone who works in my field remembers when Jennifer Doudna’s Nobel Prize winning paper came out in 2012 and we stared at those data. We read her statement at the end, this technology has considerable potential for engineering medicines. And we went, this cannot be the symbol. And yet here we are, the genius of Mother Nature in evolving CRISPR and the magnificence of Jennifer Doudna’s and Emmanuelle’s discovery is that you have basically two components. You have one protein, literally you don’t need 55 different proteins. You need one, it has a boring name, CAS9. If I were renaming it, I would call it Wonder Gift from Benevolent Mother name. That would be too long a name, right? It has the boring name CAS9, which stands for CRISPR associated gene number nine, your audience is welcome to forget this immediately. And then the way this thing works is you have to arm it with an instruction of how to go fix a gene. And that instruction looks as follows. You basically give it an envelope. It’s the same size envelope and into the envelope you put a little instruction like a little address code. And the astonishing thing is the way that addressing works is literally using rules that all of our children work and learn in elementary school about how DNA comes together, there are two strands. And if one strand says A, then the other strand says T. And if one strand says G, then you know the other strand says C. So, the way you request that CRISPR Cas9 fix your gene of interest is you basically pick 20 letters in your gene of interest and you give CAS9. You put into that little molecular envelope an RNA snippet that has a perfect match according to these A equals T and C equals G rules to that 20 letter stretch and you send it inside the cell. And then mother nature has had 3 billion years to evolve CRISPR. So she’s done a pretty amazing job. And again, the scientists, starting with Jennifer, Emmanuel, and others, have done a pretty amazing job engineering CRISPR further to where then it runs around the cell. It can be a liver cell, it can be a blood cell, it can be a brain cell, it can be a muscle cell, it can be a lung cell, an eye cell, and it just finds the gene that does its thing. So, we call it a platform because you can go from making one medicine to another by swapping out just one tiny bit. The protein is the same, the envelope is the same. The rules for writing the instructions are the same. I’ve long wanted an analogy. Is this like pizza where you bake the dough and the sauce and the cheese and then you pick your toppings. Is this ice cream where the fundamental mix is the same, but you just add pistachio versus chocolate? And honestly, none of them work because CRISPR is so much more interesting. But the basic idea is that you keep everything the same and swap out one tiny bit and bam, you get an entirely new thing. It’s fundamentally there. The federal government, I think we in America should be very proud that we have funded the National Institutes of Health, which for decades now has been led by medical innovation. And most recently, the NIH has taken a courageous step into funding five cross institutional teams to take gene editing from proof of concept all the way to the clinic using precisely this quote platform quote approach. What does that mean? Imagine a team that aims to treat diseases of the eye, congenital blindness. Now they’re caused by multiple different genes. How do you stick CRISPR in the eye? Well, first of all, you literally stick CRISPR in the eye. You have a syringe and physicians, professionals, there are legions of them in the world who know how to safely and effectively inject things into the eye. So you have CRISPR configured in a way where it will get into the eye cell successfully and it has an envelope inside it. And you have instructions to fix gene number one, that causes disease, number one. Now you pick a different disease which is caused by a different gene and you guessed it, you keep everything the same. You just swap out the instruction bit from gene one to gene two, and guess what? You have a medicine for a different disease. So, there is a team at the University of Wisconsin led by Kris Saha, which is now funded by the US federal government to take this approach to two different diseases of the eye here at the Innovative Genomics Institute. A team suggested by Jennifer Doudna is funded this way to treat two different neurodegenerative conditions. One is Huntington’s disease, one is amyotrophic lateral sclerosis, again huge partnership with UCSF and other institutions. But the fact that we have the federal government realizing the enormous impact of how, frankly, I know this is a strong word, facile it’s to go from disease one to disease two at the technical level, the federal government has recognized that and has honored five different teams. So, there’s a University of Pennsylvania, there is, as I mentioned, UC Berkeley in partnership. There’s Kris Saha at the University of Wisconsin, and others. The fact that all of these teams can now work as a consortium so we can all get together in sailing this ship across these turbulent waters where we all learn from each other. The Broad is also part of this. Manda Arbab is leading this amazing effort to treat not only spinal muscular atrophy, but then expanding to a devastating neurodevelopmental disease called rett syndrome. So the fact that we have these teams that have gotten together to do this, we are academics. We love comparing notes. It’s what we do. We grow standing on the shoulders of others and then lending the other person your own shoulder. Again, it’s just a sign of the times how amazing CRISPR is. It’s a huge unifying force.

Daniel Levine: I listened to you explain the approach and it has this elegance and simplicity to it. But what’s the challenge in taking a platform approach and scaling the development of gene editors for different diseases?

Fyodor Urnov: We have never had a technology like CRISPR. If you look at remarkable successes in the development of medicines, we have curative molecules that just generate amazing life outcomes. And they can be a small molecule, let’s say something like Tarceva for cancer, or they can be a biologic like let’s say Stelara for inflammatory bowel disease or Keytruda for cancer. They take decades to make. And again, when they work, they save lives in an extraordinary way or prolong lifespan. CRISPR, as I mentioned, designing the medicine at least on the screen is pretty fast. So suddenly this means that you can go to a catalog of genetic diseases, which is run by the federal government. It’s called OMIN online, Mendelian Inheritance in Man, you pull it down. Disease number one, pull mutation number one, click on the screen and there’s your first pass medicine. Now you pull down disease number two and there’s your first pass medicine. So suddenly we have computational biologists in the states, in Europe, down under, designing CRISPR medicines on their screen. And now what happens next? Well, what happens next is you then walk into a system for testing them and manufacturing them. That was built, let’s face it, 15 years ago. And it’s nobody’s fault. CRISPR moved so fast. Nobody was prepared for the fact that we have this amazing transportation solution, but we haven’t built the roads. Literally. We have this magnificent way to move around and it solves all problems, except that in order to move around, you have the roads, but the roads don’t exist. So, what is happening now across, to be very clear, we’re not alone at the IGI, both by a tech sector, the for-profit sector and the nonprofit sector, and partnerships such as we, are basically actively working with the regulators in the U.S., in Europe, down under, in Canada, with the manufacturers—how do we get away from a system? And I’ll just give you a specific example. So, because Casgevy, this extraordinary cure for sickle, and full disclosure—I’m a paid consultant to pharmaceuticals on Casgevy—but that doesn’t prevent me from praising it to high heaven because objectively the data are just extraordinary. The clinical data, you take the recipe for Casgevy and you tweak one thing and you have a medicine for a rare inborn error of immunity. But the problem is that that disease affects 50 kids, right? 50 kids worldwide, whereas sickle affects millions. So now the question becomes, how do you take the Casgevy recipe, which we know is out there and brew a different medicine? Well, on paper it looks fast, but in practice, we’re back to square one and we need four to five years and we need tens of millions of dollars. Who exactly is going to invent $10 million to invest in treating 50 kids? I mean, the goodness of our heart wants to do that, but that’s just not the world we live in. So, the first thing that needs to happen is we need to think of CRISPR not as a medicine for one disease, but as a medicine for entire constellations of diseases and build a framework where in going from disease one to disease two, we have a cookbook. Literally the Joy of Cooking. Imagine the Joy of CRISPR. And the great thing about that book or any proper cookbook is there’s like a base recipe, like here’s a recipe for dough, here’s a recipe for broth, whatever. And now if you want to make something out of that dough, you add a filling or you add something you put into your broth. And we need that cookbook to be scalable. It needs to rely on commonly available manufacturable components and needs standardized protocols that critically everyone can use, right? Industry, academia, for-profit, wherever you are, you can gain access to the Joy of CRISPR and download the recipe for how to treat a set of syndromes that affect the liver, that affect the eye, that affect the brain, that affect the blood. And I want to emphasize this is not a disheveled academic on the UC Berkeley campus pontificating inside an ivory tower. I mean, there’s consensus across everyone in the field that we have to get to this world. The question is how. And so, the answer is we have to lead in an academic nonprofit sector because by nature we are intrinsically more collaborative, because we’re in what’s called pre-competitive space. So what we’re currently doing is writing that cookbook. And here at the IGI, we partnered with Danaher to write that cookbook for inborn errors of immunity. The team at Penn Medicine, funded by the NIH and led by Kiran Musunuru, is doing that for liver disease. I mentioned Chris Saha at Wisconsin, who is doing that for congenital diseases of the eye, Manda Arbar at the Broad is doing this for neurodegenerative disorders. And our team at the IGI is doing this for other neurodegenerative disease. So, we have a lot of momentum in the not-for-profit academic sector. And I should also emphasize that we have really tremendous efforts of this type in the United Kingdom. For example, in the European Union, like in Italy for example, the Italians have historically really led the charge in genetic therapy for various diseases. And again, I salute the government and the scientists and physicians there for having done a really impressive job. So all of us in this academic nonprofit community are writing chapters of this cookbook in real time and exchanging notes. And critically, we’re not just putting out white papers and being proud of ourselves. We’re actively working to put that into the clinic, whether with federal support or state support or with support from our partners such as Danaher. Once the regulators in the U.S., in the U.K., in the EU, down under, see the promise, like these solutions that the recipes from this cookbook have been in people, my dream honestly is for the for-profit sector to take it wholesale please. I want Lilly, I want GSK, Johnson & Johnson, Merck, Moderna, all of these, Vertex has already entered into this space vigorously, right? Regeneron, all of these companies, please take the cookbooks, your various additions, and please apply them both to rare genetic diseases and larger disease indications. For example, I mentioned cardiovascular disease. It’s a huge problem in disorders of the immune system. We at the IGI in partnership with UCSF and UCLA and Danaher are doing immune system engineering for genetic disorders. There are ways to tweak the immune system to treat inflammatory bowel disease, which is a much, much, much larger indication than genetic diseases of the immune system. But in order to do that successfully, you need a large company with enough muscle to do drug development and ultimately clinical trials for an indication of the size of IBD. That’s really my dream that we, academics and nonprofits, in creative partnerships build cookbooks that ultimately get taken by the for-profit sector and it runs with it.

Daniel Levine: Let’s talk about the agreement with Danaher. Under the collaboration, the two organizations are creating a collaborative center to develop gene editing therapies for rare and other diseases. This is the Danaher IGI Beacon for CRISPR Cures. What does each organization bring to the collaboration?

Fyodor Urnov: My favorite book as a child was the Three Musketeers, and I loved it for the teamwork, the one for all and all for one, but also the fact that the three characters have non-overlapping superpowers, right? Athos is wise, Portos is big, and swashbuckling, Artemis is cunning, and D’Artagnan is just ridiculously brave. And so in present day analogies, I think, I guess I would say the Avengers is the analogy, right? You have superheroes with non-overlapping superpowers. I honestly think of the IGI Danaher partnership as this kind of Avengers like alliance, right? And Danaher has brought together companies that manufacture nearly every solution that we CRISPR people need. So if you imagine an amazing supermarket, those familiar with the Bay Area, there’s this amazing organic supermarket called the Berkeley Bowl, and you can literally get every kind of fruit and vegetable that exists. So, for me, as a gene editor, Danaher companies kind of are going into that, right? Do I want some Cas9? I turn to Aldeveron. Do I need some lipid nanoparticles? I turn to Precision Nanosystems. Do I need a sophisticated microscope to look at edited cells? I have Leica, et cetera, IDT, et cetera. I can go on and on and on. Okay, but what are we? We are CRISPR people. We know how to make CRISPR medicines, but critically, we at the IGI are basically scientists. We sit in front of transparent test tubes and we need to be sitting in front of patients. And here again, I cannot say to you how deeply grateful I am to UCSF, our partners across the Bay, and UCLA, and they are magnificent centers of clinical excellence who have invested decades of experience in building infrastructure for both bringing in patients with genetic diseases and for treating them with experimental medicines. So, physicians like Jennifer Puck, and more, Kunwar at UCSF who treat devastating disorders of the entirety of the immune system, or Michelle Hermiston, who treats a different category of devastating disorders of the immune system, or Donald Kohnn at UCLA, who is one of the world leaders at building gene therapies for these and also manufacturing the cells. So, to be clear, if you think about the Avengers analogy, we have a very focused superpower. We are CRISPR people, but okay, fine. We have the world’s most beautiful CRISPR for disease number one in a test tube on the UC Berkeley campus now. So now what happens is we have people who know how to make edited cells at UCSF and UCLA, and we have clinicians with the depth of bringing them in. So where does Danaher come in? Danaher is literally the provider of every technology solution that we need to move this forward. But I want to be clear, this isn’t one of those, “Hey, Danaher, send us a vial of CRISPR and go back to what you were doing.” The beautiful thing about this partnership, why I’m excited about this, is a partnership. So, everything that Danaher companies make is built by scientists like myself—literally people whose favorite way to pass time is move transparent liquids between transparent tubes. Ultimately we’re building medicines. And so in every interaction I’ve had with folks at Danaher companies, Aldeveron, IDT, Cytiva, Precision Nanosystems, like Beckman Coulter—it’s just been such a meeting of kindred spirits and people with the right kind of heart. We’re all wearing lab coats stained with various experiments past, and we are all obsessed with our data. And to be able to join forces and blurring this industry/academia boundary to say, look we need to build the world’s most specific CRISPR that would be manufacturable at scale to give to clinicians at UCSF to treat these devastating diseases. I mean, the spirit that drives us is completely congruent and completely united. I often use the word first-in-class, and you also have to be careful, always have to be careful about overpraising yourself. I don’t really know of another example where a company the size of Danaher would support an organization constellation so formidable as the IGI and UCSF and UCLA in something that is so motivated by frankly, goodness of the heart. Because the diseases we’re aiming to treat affect 10, 20, 30, 40, 50 children. And again, not exactly a million patient indication. Why are we doing this? Because our explicit focus from day one is how do we do the design, manufacturing and clinical deployment in a way where a new patient comes into Michelle Hermiston’s clinic and it’s a new mutation we have never seen before. This kid has six months to live, and you speak with Michelle Hermiston about what it’s like for her to treat these dying children. And you get out a box of Kleenex. I mean, I literally break up, I choke up when I listen to her speak, and here we are. We have six months, right? This kid has a new mutation, needs a brand new CRISPR under the current system that CRISPR takes four years and $10 million. This kid has six months. So, we are working towards a world where the manufacturing and engineering might of Danaher and the CRISPR ingenuity of the IGI and the technical and clinical wizardry of manufacturers at UCSF and UCLA, cell manufacturers. And the clinicians can join forces and say, look, we have a child. We have four months. Let’s go. But ultimately, this cannot be a setting where you summon a hundred person strong team and invest tens of millions. We have to get to a world where this effort is scalable. We make pizzas with different toppings. Thank you very much. And it’s scalable to where the cost of goods are dramatically reduced. I want to emphasize, I don’t want to overpromise and under deliver. We are at the start of a four year partnership, but you always want to be mindful that you’re bringing all the right people and all the right gear on a journey like this. Looking at the lineup of Team Beacon across ICI, UCSF, and UCLA, and of course at the folks we’ve partnered with at Danaher, we have the right team and the right, I don’t want to say ship, because ship seems very 12th century. We have the right levitating hovercraft to take on this unprecedented journey.

Daniel Levine: This is not the first “beacon” that Danaher created. Did you look to the other beacons to learn from them at all?

Fyodor Urnov: My goodness, when we spoke with Danaher about this, we were frankly awestruck in a healthy way by the kind of partnerships they’ve signed. They have a partnership with Duke, and not only does Duke need no introduction, but the specific scientific lead at Duke who heads that beacon is a superhero. Danaher has a partnership with Penn Medicine, and the person they’re working with just won the Breakthrough Prize, Carl June. And so when Jennifer Doudna and IGI leadership and yours truly were sitting down and planning ahead, and we looked at Danaher’s vision and bringing in superheroes frankly in our space to team up, we said to ourselves, yeah, this is a constellation of efforts we want be part of. And yes, it’s just been so gratifying to connect with in a deeper way with our colleagues at the frontiers of the genetic medicine space and realize that we have now been connected. Obviously, Duke is in North Carolina, Penn Medicine is in Pennsylvania, and we are in California. But the threads that connect us are very strong, and they are vibrant threads. It’s not just a set of emails. There is a team spirit across the Beacons where the standard analogy I make is we bring together the quote “one plus one equals seven” non additive arithmetic.

Daniel Levine: The idea here is to develop a unified approach to research development and a regulatory approach to industrialize the process of creating and bringing CRISPR therapies to patients. This is a big and complex lift. Are there other collaborators involved?

Fyodor Urnov: So, my and our—I really should really stop using the first person pronoun because of course, it’s a huge team. It’s been deeply gratifying to speak both with Danaher and our colleagues across the landscape of academic and gene editing medicine about how to make the Beacon halo larger. And this involves both groups in the United States at places like Boston Children’s and St. Jude, for example. Again, everybody knows St. Jude for the extraordinary work that they have done to humanize the face of childhood disease and make nonprofit solutions viable. It’ll not surprise your audience that St. Jude is a leader in gene editing, and we’re in really active discussions about how to team up under the benevolent halo of the Beacon, and also to have been able to reach out to the U.K. The United Kingdom over the past few years has become sort of an unofficial leader in es-US innovation in genetic therapy space. The regulators in the United Kingdom have frankly shown some formidably clear vision of what it needs, what the world needs to move things forward And genetic diseases know no boundaries, right? It’s not like there’s, this is a U.S. disorder. There’s no such thing. There are folks in the United Kingdom suffering from these kinds of conditions just as deeply as they are in the States or New Zealand. So yes, absolutely. While the Beacon itself has a specific set of participants and a specific set of diseases, it really warms my heart that our colleagues at Danaher thoroughly welcome the notion that as we develop solutions and as we grow the clinic-bound programs, that we can start to disseminate and share and team up broadly. The community of clinicians and scientists who are building CRISPR cures is really large. And the siloization that’s existed so far is not by design. Nobody wants to work separately from anybody else. It’s just that there has never been the momentum or frankly the resources to start to team up in cross multinational ways. Again, I mentioned earlier that eradication of smallpox took humanity coming together in an unprecedented way. I am not that delusional. Oh, in 10 years, humanity will come together and all 300 million people across the world who have genetic diseases will have been CRISPRed to health. No, but we have to take a first formidable step, and that means building scalable, affordable solutions, teaming up their engineering and deployment across nations and forward integrating everything we do to being able to deliver these to parts of the world where the public health burden of these diseases is quite high—Brazil, Sub-Saharan Africa, the Middle East. Asia. I learned from Dr. Hermiston at UCSF that there is a formidable population of folks with a specific condition we’re treating called HLH in Vietnam. That’s step one, I’m sorry, step two, like let’s build this and then actively work with the health authorities, with the government, with the regulators, and of course with our partners here. What will it take to expand the impact of our California engineered cure for this disease into a country where there’s a formidable public health burden, but not yet the infrastructure to design their own? Ultimately, we have to empower the world. Look, I really admire, for example, what folks in India have done. There’s just been a really impressive effort to develop what they call their “work play not mind” indigenous solutions to manufacturing cancer immunotherapies of the CAR T class in India where they’ve been able to be very clear. These are sort of classical CAR T gene therapy for cancer, not gene editing, but still they make their own and they treat patients at a fraction of the cost, and good for them. I really think that ultimately empowering the physicians of the world and the scientists of the world to make their own is the way forward. We are years away from that, but this is the trajectory we’re on.

Daniel Levine: The initial focus is on developing gene editing therapies for two rare genetic inborn errors of immunity. These are hemophagocytic, lymphohistiocytosis (HLH), and Artemis SCID. Why start here?

Fyodor Urnov: Three reasons. We cannot swing for the impossible. It would be wrong of us to look at our partners at Danaher or our colleagues at UCSF and UCLA and say, you know what? Let’s fix the brain. We want to fix the brain. Chris Hemsworth has gone public, talk about superheroes. He has a genetic mutation, APOE4. He’s homozygous for the APOE4. If he lives to 60 or 70, he has a very high chance of developing currently incurable Alzheimer’s. We’re not going for that. Why? Not because we don’t want to, but because we can’t. So we needed to go for something that we could actually deliver on in the next few years because as I mentioned, it’s imperative that we test drive these solutions both developed here and in partnership with Danaher in the real world of the clinic. That’s goal number one.

Goal number two, areas of severe unmet medical need, which the for-profit sector does not take on—a central mandate of the IGI. Again, when I spoke with Jennifer Doudna about her vision for the IGI, she said to me, “Fyodor, we have to make CRISPR available to all those who need it, not just those who can afford it.” Jennifer herself has said, again, when I repeat her words, I literally get goosebumps. She said, “Look, a $3 million cure for a genetic disease, is that really a cure?” I know what she means. Who can afford that? So we are focusing on diseases that frankly have no commercial value right now in terms of cure. Now we want the world to change in that regard, but it’ll not change in the next few years while patients continue to suffer. And three, we have to rely on clinical excellence of our partners—that here we are in our test tubes and our spectrophotometers and our gel electrophoresis equipment, very proud of ourselves of how great our CRISPR is. But the hardest part is the clinical side, like working with a patient, bringing them in, bringing the family, speaking with them, designing a clinical trial where it would honor all the ethical rules for how to do that, making sure that the patients are treated according to the highest standard of clinical care and then the follow-up is done properly. That is an art; that is in a whole different level of complexity than anything we little protein engineers can ever do. And so, the fact that our partners at UCSF are superheroes in that regard and that they have this, I don’t want to say magical touch because there’s nothing magical about it, but I certainly experienced it as magical and is what drove this, right? The clinicians came to us and said, look, let me tell you about Artemis Skid. It affects disproportionately and tragically children of the Navajo nation. Nobody’s going to work on commercializing this cure, but we are working on that. Do you want to work on a CRISPR for it? And we said, oh, yes, please. So those are the three criteria feasibility. Then nobody in the for-profit sector is going to work for that so it’s already three clinical excellence. And last, but perhaps I should have said first, there are 505 different inborn errors of immunity. There’s not a single CRISPR trial for a single one of them. The platform concept is on prime display. In our effort, if at the end of the four years we have written a recipe for two cures, we will have failed. The idea is to take two curative treatments to the clinic to see if they’re indeed curative, but also to have written a cookbook where physicians and scientists across the world over can start to use that cookbook to build medicines, diseases three through 48 and then 49 through 96 and so on and so on. So it’s the platform aspect.

Daniel Levine: How does manufacturing fit into the issue of scalability of these therapies then? Will there be any effort to address that in this partnership?

Fyodor Urnov: Absolutely. Right now, if I have a medicine that I need to use to treat 20,000 people with sickle cell disease, or if I need to manufacture a medicine that will be used to treat 50 children, the manufacturing process and standards for that are essentially equivalent and I’m not trying to be critical. I’m just describing the state of the world. The challenge here is that for many devastating disorders where children have months to live in order to meet those manufacturing standards, we will have spent more time and money than the child has or anybody with any kind of wallet has. So, the way forward here is to develop a new way to manufacture these medicines that is acutely respectful of safety/quality, but is also mindful of the benefit/risk. In brief, we cannot have a two year process to make and quality control a CRISPR medicine for a child who has six months to live. We’ve never had to solve this problem because we’ve never had a technology that is in principle scalable to that kind of speed. I’m a tool builder. I’m an engineer, but I’m an engineer of molecular level things. It excites me. This challenge excites me. How do we re-engineer the manufacturing system for the medicine itself to where we can meet all standards? To be clear, the goal is not to home brew stuff in our garage and inject it into suffering children. One hundred percent of what we do will be reviewed. Every syllable will be reviewed by the Food and Drug Administration, by the MHRA in the U.K, by the EMA in Europe, et cetera. But the goal is to work with the regulators and the manufacturers. Again, welcome Danaher who can make enough of this material to treat the world and say, “Can we come up with an accelerated scalable framework where the cost of goods of making these and the timeline to making these is much shorter than what it currently is?” And I want to be clear. If you sit with the world’s best experts around the table today and say, “write a solution,” we wouldn’t know what that is. This is why the Beacon is a four-year process. We have committed to teaming up with Danaher leads on manufacturing these and speaking with the Food and Drug Administration vigorously and rigorously in saying to them, “Hi, here we are, work with us.” And I really want to credit the FDA. All engagements so far with the Center for Biologics Evaluation Research, which is led by Peter Marks, have been tremendously positive that the FDA really understands what the joint problem is. And to their tremendous credit, they do not experience this as our problem, they experience this as our joint problem. And it’s frankly refreshing. one thinks of regulators as these faceless humans in a building somewhere that don’t care. Nothing could be further from the truth. The FDA cares. They really do. And we’re very fortunate to have, again, leadership. I should also say every time I speak with Peter Marks, like say in a conference, I thank him publicly for his leadership of the CBER basically to getting the vaccines put through clinical trials and approved. I got jabbed five times and thank you. Thank you, Pfizer. Thank you, but thank you the FDA. and I think in some sense, I shouldn’t speak for them. It sounds like the FDA’s kind of encouraged that they’ve pulled off this amazing thing. They’re kind of in the mindset that they should be building innovative solutions in regulatory manufacturing space, which would be scalable. Now, to be clear, the Covid pandemic is very different mechanistically than what we’re currently dealing with in the genetic disease space. But what I’m saying is the mindset, right? The way the agency, I think, is thinking about this, there is a very hashtag “yes we can” attitude and a collaborative attitude, which I really appreciate. It’s been good. Again, ask me again in two years. In two years, I might start complaining, but so far we riding on a bit of euphoria.

Daniel Levine: Ultimately, is there a plan for pushing out or sharing what’s learned from this effort so other therapeutic developers can benefit from it?

Fyodor Urnov: One hundred percent. We’re an institution of the State of California. If you go to the Berkeley campus, the very first thing you’ll see is the Campanile, which is our beautiful tower. But the landmark is of course, Sather Gate, which leads you into campus and over Sather Gate is our university’s motto, “Let There Be Light.” What does that mean? It means our job, literally, number one, the number one line of our job description is our work has to benefit our state, our nation, or the planet. So sharing across academia, nonprofits, and ultimately across industry is rule number one. The for-profit sector inherently has a competitive component, and I’m not trying to change that. That’s how it is. But the not-for-profit sector inherently has a “we are all in this boat together”feature. And so absolutely the cookbook will be a living document and will be available to our colleagues in academia and nonprofits and ultimately industry. We’re not trying to put the CRISPR cure solution manual in a safe somewhere under the IGI. We want to put it onto a server with a hyperlink. Really, that’s the goal. That’s the goal.

Daniel Levine: Fyodor Urnov, director of Technology and Translation for the Innovative Genomics Institute. Fyodor, thanks as always.

Fyodor Urnov: Such a pleasure to speak with you. I really appreciate you being willing to take time to report on this and share this with your audience.

This transcript has been lightly edited for clarity and readability.


The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.





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