Exploring the Impact of Basic Science in Rare Pediatric Diseases

Eric Topol (00:05):

Hello, it's Eric Topol from Ground Truths, and I've got some really exciting stuff to talk to you about today. And it's about the announcement for a new Center for pediatric CRISPR Cures. And I'm delight to introduce doctors Jennifer Doudna and Priscilla Chan. And so, first let me say this is amazing to see this thing going forward. It's an outgrowth of a New England Journal paper and monumental report on CRISPR in May. [See the below post for more context]

Let me introduce first, Dr. Doudna. Jennifer is the Li Ka Shing Chancellor's Chair and a Professor in the departments of chemistry and of molecular and cell biology at the University of California Berkeley. She's also the subject of this book, one of my favorite books of all time, the Code Breaker. And as you know, the 2020 Nobel Prize laureate for her work in CRISPR-Cas9 genome editing, and she founded the Innovative Genomics Institute (IGI) back 10 years ago. So Jennifer, welcome.

Jennifer Doudna (01:08):

Thank you, Eric. Great to be here.

Eric Topol (01:10):

And now Dr. Priscilla Chan, who is the co-founder of the Chan Zuckerberg Initiative (CZI) that also was started back in 2015. So here we are, a decade later, these two leaders. She is a pediatrician having trained at UCSF and is committed to the initiative which has as its mission statement, “to make it possible to cure, prevent, and manage all diseases in this century.” So today we're going to talk about a step closer to that. Welcome, Priscilla.

Priscilla Chan (01:44):

Thank you. Thanks for having me.

Eric Topol (01:46):

Alright, so I thought we'd start off by, how did you two get together? Have you known each other for over this past decade since you both got all your things going?

Jennifer Doudna (01:56):

Yes, we have. We've known each other for a while. And of course, I've admired the progress at the CZI on fundamental science. I was an advisor very early on and I think actually that's how we got to know each other. Right, Priscilla?

Priscilla Chan (02:11):

Yeah, that's right. We got to know each other then. And we've been crisscrossing paths. And I personally remember the day you won the Nobel Prize. It was in the heart of the pandemic and a lot of celebrations were happening over Zoom. And I grabbed my then 5-year-old and got onto the UCSF celebration and I was like, look, this is happening. And it was really cool for me and for my daughter.

Eric Topol (02:46):

Well, it's pretty remarkable convergence leading up to today's announcement, but I know Priscilla, that you've been active in this rare disease space, you've had at CZI a Rare As One Project. Maybe you could tell us a bit about that.

Priscilla Chan (03:01):

Yeah, so at CZI, we work on basic science research, and I think that often surprises people because they know that I'm a pediatrician. And so, they often think, oh, you must work in healthcare or healthcare delivery. And we've actually chosen very intentionally to work in basic science research. In part because my training as a pediatrician at UCSF. As you both know, UCSF is a tertiary coronary care center where we see very unusual and rare cases of pediatric presentations. And it was there where I learned how little we knew about rare diseases and diseases in general and how powerful patients were. And that research was the pipeline for hope and for new discoveries for these families that often otherwise don't have very much access to treatments or cures. They have a PDF that maybe describes what their child has. And so, I decided to invest in basic science through CZI, but always saw the power of bringing rare disease patient cohorts. One, because if you've ever met a parent of a child with rare disease, they are a force to be reckoned with. Two, they can make research so much better due to their insights as patients and patient advocates. And I think they close the distance between basic science and impact in patients. And so, we've been working on that since 2019 and has been a passion of ours.

Eric Topol (04:40):

Wow, that's great. Now Jennifer, this IGI that you founded a decade ago, it's doing all kinds of things that are even well beyond rare diseases. We recently spoke, I know on Ground Truths about things as diverse as editing the gut microbiome in asthma and potentially someday Alzheimer’s. But here you were very much involved at IGI with the baby KJ Muldoon. Maybe you could take us through this because this is such an extraordinary advance in the whole CRISPR Cures story.

Jennifer Doudna (05:18):

Yes, Eric. It's a very exciting story and we're very, very proud of the teamwork that went into making it possible to cure baby KJ of his very rare disease. And in brief, the story began back in August of last year when he was born with a metabolic disorder that prevented him from digesting protein, it's called a urea cycle disorder and rare, but extremely severe. And to the point where he was in the ICU and facing a very, very difficult prognosis. And so, fortunately his clinical team at Children's Hospital of Philadelphia (CHOP) reached out to Fyodor Urnov, who is the Director of Translational Medicine at the IGI here in the Bay Area. They teamed up and realized that they could quickly diagnose that child because we had an IRB approved here at the IGI that allowed us to collect patient samples and do diagnosis. So that was done.

Jennifer Doudna (06:26):

We created an off-the-shelf CRISPR therapy that would be targeted to the exact mutation that caused that young boy's disease. And then we worked with the FDA in Washington to make sure that we could very safely proceed with testing of that therapy initially in the lab and then ultimately in two different animal models. And then we opened a clinical trial that allowed that boy to be enrolled with, of course his parents' approval and for him to be dosed and the result was spectacular. And in fact, he was released from the hospital recently as a happy, healthy child, gaining lots of weight and looking very chunky. So it's really exciting.

Eric Topol (07:16):

It's so amazing. I don't think people necessarily grasp this. This timeline [see above] that we'll post with this is just mind boggling how you could, as you said Jennifer, in about six months to go from the birth and sequencing through cell specific cultures with the genome mutations through multiple experimental models with non-human primates even, looking at off-target effects, through the multiple FDA reviews and then dosing, cumulatively three dosing to save this baby's life. It really just amazing. Now that is a template. And before we go to this new Center, I just wanted to also mention not just the timeline of compression, which is unimaginable and the partnership that you've had at IGI with I guess Danaher to help manufacture, which is just another part of the story. But also the fact that you're not just even with CRISPR 1.0 as being used in approvals previously for sickle cell and β-thalassemia, but now we're talking about base editing in vivo in the body using mRNA delivery. So maybe you could comment on that, Jennifer.

Jennifer Doudna (08:38):

Yeah, very good point. So yeah, we used a version of CRISPR that was created by David Liu at the Broad Institute and published and available. And so, it was possible to create that, again, targeted to the exact mutation that caused baby KJ’s disease. And fortunately, there was also an off-the-shelf way to deliver it because we had access to lipid nanoparticles that were developed for other purposes including vaccinations. And the type of disease that KJ suffered from is one that is treatable by editing cells in the liver, which is where the lipid nanoparticle naturally goes. So there were definitely some serendipity here, but it was amazing how all of these pieces were available. We just had to pull them together to create this therapy.

Eric Topol (09:30):

Yeah, no, it is amazing. So that I think is a great substrate for starting a new Center. And so, maybe back to you Priscilla, as to what your vision was when working with Jennifer and IGI to go through with this.

Priscilla Chan (09:45):

I think the thing that's incredibly exciting, you mentioned that at CZI our mission is to cure, prevent, and manage all disease. And when we talked about this 10 years ago, it felt like this far off idea, but every day it seems closer and closer. And I think the part that's super exciting about this is the direct connection between the basic science that's happening in CRISPR and the molecular and down to the nucleotide understanding of these mutations and the ability to correct them. And I think many of us, our imaginations have included this possibility, but it's very exciting that it has happened with baby KJ and CHOP. And we need to be able to do the work to understand how we can treat more patients this way, how to understand the obstacles, unblock them, streamline the process, bring down the cost, so that we better understand this pathway for treatment, as well as to increasingly democratize access to this type of platform. And so, our hope is to be able to do that. Take the work and inspiration that IGI and the team at CHOP have done and continue to push forward and to look at more cases, look at more organ systems. We're going to be looking in addition to the liver, at the bone marrow and the immune system.

Priscilla Chan (11:17):

And to be able to really work through more of the steps so that we can bring this to more families and patients.

Eric Topol (11:30):

Yeah, well it's pretty remarkable because here you have incurable ultra-rare diseases. If you can help these babies, just think of what this could do in a much broader context. I mean there a lot of common diseases have their roots with some of these very rare ones. So how do you see going forward, Jennifer, as to where you UC Berkeley, Gladstone, UCSF. I'm envious of you all up there in Northern California I have to say, will pull this off. How will you get the first similar case to KJ Muldoon going forward?

Jennifer Doudna (12:13):

Right. Well, IGI is a joint institute, as you probably know, Eric. So we were founded 10 years ago as a joint institute between UC Berkeley and UCSF. And now we have a third campus partner, UC Davis and we have the Gladstone Institute. So we've got an extraordinary group of clinicians and researchers that are coming together for this project and the Center to make it a success. We are building a clinical team at UCSF. We have several extraordinary leaders including Jennifer Puck and Chris Dvorak, and they are both going to be involved in identifying patients that could be enrolled in this program based on their diagnosis. And we will have a clinical advisory group that will help with that as well. So we'll be vetting patients probably right after we announce this, we're going to be looking to start enrolling people who might need this type of help.

Eric Topol (13:18):

Do you think it's possible to go any faster right now than the six months that it took for KJ?

Jennifer Doudna (13:26):

I think it could be. And here's the reason. There's a very interesting possibility that because of the type of technology that we're talking about with CRISPR, which fundamentally, and you and I have talked about this previously on your other podcast. But we've talked about the fact that it's a programmable technology and that means that we can change one aspect of it, one piece of it, which is a piece of a molecule called RNA that's able to direct CRISPR to the right sequence where we want to do editing and not change anything else about it. The protein, the CRISPR protein stays the same, the delivery vehicle stays the same, everything else stays the same. And so, we're working right now with FDA to get a platform designation for CRISPR that might allow streamlining of the testing process in some cases. So it'll obviously come down to the details of the disease, but we're hopeful that in the end it will be possible. And Priscilla and I have talked about this too, that as AI continues to advance and we get more and more information about rare diseases, we'll be able to predict accurately the effects of editing. And so, in some cases in the future it may be possible to streamline the testing process even further safely.

Eric Topol (14:51):

And I also would note, as you both know, well this administration is really keen on genome editing and they've had a joint announcement regarding their support. And in my discussions with the FDA commissioner, this is something they are very excited about. So the timing of the new Center for pediatric CRISPR Cures is aligned with the current administration, which is good to see. It's not always the case. Now going back, Priscilla, to your point that not just for the liver because delivery has been an issue of course, and we're going to try to get after a lot of these really rare diseases, it's going to go beyond there. So this is also an exciting new dimension of the Center, as you said, to go after the bone marrow for hematopoietic cells, perhaps other organs as well.

Priscilla Chan (15:42):

I mean what the expertise and feasibility, the immune system is going to be the next target. Jennifer Puck has been a pioneer in this work. She's the one who designed the newborn screen that will be the tool that picks up these patients as they are born. And I think the thing that's tremendous is the immune system, first of all is active in many, many diseases, not just these cases of children born with partial or absence of immune systems. And the course right now that these babies are left with is complete isolation and then a very long and arduous course of a bone marrow transplant with high morbidity and mortality. And even if after the transplant you have complications like graft versus host and immunosuppression. And so, the idea of being able to very specifically and with less the conditioning and morbidity and mortality of the treatment, being able to address this is incredible. And the implications for other diseases like blood cancers or other hematopoietic diseases, that's incredible. And that actually has an incredibly broad base of patients that can benefit from the learnings from these babies with severe combined immunodeficiencies.

Eric Topol (17:10):

Yeah, I think that goes back to a point earlier maybe to amplify in that previous CRISPR generation, it required outside the body work and it was extremely laborious and time consuming and obviously added much more to the expense because of hospitalization time. This is different. This is basically doing this inside the affected patient's body. And that is one of the biggest reasons why this is a big step forward and why we're so fortunate that your Center is moving forward. Maybe before we wrap up, you might want to comment, Jennifer on how you were able to bring in to build this platform, the manufacturing arm of it, because that seems to be yet another dimension that's helpful.

Jennifer Doudna (18:01):

Indeed, yes. And we were again fortunate with timing because you mentioned briefly that the IGI had set up a program with the Danaher Corporation back in January of last year. We call it our Beacon project. And it's focused on rare disease. And it's a really interesting kind of a unique partnership because Danaher is a manufacturing conglomerate. So they have companies that make molecules, they make proteins, they make RNA molecules, they make delivery molecules. And so, they were excited to be involved with us because they want to be a provider of these types of therapies in the future. And they can see the future of CRISPR is very exciting. It's expanding, growing area. And so, that agreement was in place already when the baby KJ case came to our attention. And so, what we're hoping to do with Danaher is again, work with them and their scientists to continue to ask, how can we reduce the cost of these therapies by reducing the cost of the molecules that are necessary, how to make them efficiently. We already, it's very interesting, Fyodor Urnov has toured their plant in North Dakota recently, and he found in talking to their engineers, there are a number of things that we can already see will be possible to do that are going to make the process of manufacturing these molecules faster and cheaper by a lot.

Eric Topol (19:28):

Wow.

Jennifer Doudna (19:28):

So it's a win-win for everybody. And so, we're really excited to do that in the context of this new Center.

Eric Topol (19:36):

Oh, that's phenomenal because some of these disorders you don't have that much time to work with before they could be brain or organ or vital tissue damage. So that's great to hear that. What you built here is the significance of it can't be under emphasized, I'll say because we have this May report of baby KJ, which could have been a one-off and it could have been years before we saw another cure of an ultra-rare disorder. And what you're doing here is insurance against that. You're going to have many more cracks at this. And I think this is the excitement about having a new dedicated Center. So just in closing, maybe some remarks from you Priscilla.

Priscilla Chan (20:24):

I just want to emphasize one point that's really exciting as we talk about these ultra-rare cases that they're often like one in a million. All these learnings actually help maximize the impact of lots of research across the sector that impacts actually everyone's health. And so, our learnings here from these patients that have very significant presentations that really can stand to benefit from any treatment is hopefully paving the way for many, many more of us to be able to live healthier, higher quality lives through basic science.

Eric Topol (21:13):

And over to you, Jennifer.

Jennifer Doudna (21:15):

Couldn't agree more. It's a really interesting moment. I think what we hope we are, is we're at sort of an inflection point where, as I mentioned earlier, all the pieces are in place to do this kind of therapeutic and we just need a team that will focus on doing it and pulling it together. And also learning from that process so that as Priscilla just said, we are ultimately able to use the same strategy for other diseases and potentially for diseases that affect lots of people. So it's exciting.

Eric Topol (21:46):

For sure. Now, if I could just sum up, this is now a decade past the origination of your work of CRISPR and how already at the first decade culminated in sickle cell disease treatment and β-thalassemia. Now we're into the second decade of CRISPR. And look what we've seen, something that was unimaginable until it actually happened and was reported just a little over a month ago. Now going back to Priscilla's point, we're talking about thousands of different rare Mendelian genomic disorders, thousands of them. And if you add them all up of rare diseases, we're talking about hundreds of millions of people affected around the world. So this is a foray into something much bigger, no less the fact that some of these rare mutations are shared by common diseases and approaches. So this really big stuff, congratulations to both of you and your organizations, the Innovative Genomics Institute and the Chan Zuckerberg Initiative for taking this on. We'll be following it with very deep interest, thank you.

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