With its potential to expand the horizons of what’s possible for patients, CRISPR is the new darling of biotech. Reaching an important milestone in 2023 with the FDA approval of a sickle cell treatment using CRISPR, the technology is poised to break new barriers for treating patients in the near future. In this episode we talk with two companies working together on the next generation of CRISPR: editing cells within the body. We discuss the progress and the challenge in making this breakthrough a reality.
With its potential to expand the horizons of what’s possible for patients, CRISPR is the new darling of biotech. Reaching an important milestone in 2023 with the FDA approval of a sickle cell treatment using CRISPR, the technology is poised to break new barriers for treating patients in the near future. In this episode we talk with two companies working together on the next generation of CRISPR: editing cells within the body. We discuss the progress and the challenge in making this breakthrough a reality.
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Theresa Brady (00:05):
Listeners to our show know that we cover scientific breakthroughs that can change and improve people's lives. And there is nothing more revolutionary and exciting than CRISPR technology, which continues to advance, expanding the horizons of what's possible for patients. During this season alone, we've covered the first FDA approved, CRISPR based gene editing therapy for sickle cell disease.
(00:31):
We also covered the application of CRISPR technology to the study of the microbiome. And last year, we aired a podcast called The New Age of CRISPR. Increasingly, this new frontier is moving towards gene editing within the human body.
Speaker 2 (00:48):
For the first time, our programs are testing CRISPR-Cas9 experimental treatments that are systemically delivered, which means the treatment is delivered intravenously, or into the veins, to edit disease causing genes.
Theresa Brady (01:04):
But we didn't get here overnight. Biological systems are complex, which means the road from discovery to commercialization is a long one, full of twists and turns.
Speaker 3 (01:15):
But did you know, the very first person to introduce the possibility of gene editing was a 28-year-old student named Francisco Mojica, who was doing his doctorate at the University of Alicante in Spain in 1992. Eventually, in 2005, his findings were published in the Journal of Molecular Evolution. It took until 2007 before many in the scientific community began to recognize the importance of the bacterial immune response and its potential in gene editing.
Theresa Brady (01:45):
After that, the research proliferated and we now have dozens of companies engaged in some aspect of CRISPR technology. Today we talk with two companies who are collaborating on this next application of CRISPR, editing cells within the body. I'm Theresa Brady and you're listening to I Am Bio. For those of us who suffer from diseases or who have loved ones who do, we want treatments and cures as soon as possible. Time is precious. But we can't force the scientific process. It requires understanding the underlying biological mechanisms of diseases, and then testing and retesting to determine if the treatment is safe and if it actually works.
(02:45):
CRISPR-Cas9 burst onto the scene around 2010. The first FDA approval for a treatment using the technology came at the end of 2023, more than a decade later. Now, there are over 100 clinical trials underway to use CRISPR to treat both rare and prevalent diseases. Biotech companies are racing against time to find treatments and cures and the prognosis is promising. As we talked about on another episode, patients using the FDA approved drug for sickle cell disease, Casgevy, must go through an ex-vivo procedure, which means cells are extracted from the body, edited, and then reinserted. David Altshuler of Vertex, the company that produces Casgevy described for us what the ex vivo procedure entails.
David Altshuler (03:40):
Casgevy does involve a fairly significant experience for the patient and the doctors. The process involves three steps, each of which can take months. The first step is actually for the patient to work with their doctor and their family and to decide if this is right for them, to learn about it, to undergo testing, to see if they have all the different things checked that need to be checked and to decide to proceed.
(04:04):
The second step is to collect stem cells from their blood. They're shipped to a facility where they have the gene editing done, and then the cells are checked for quality and that everything's ready, and then they're shipped back to the doctor. The third step is a bone marrow transplant. In order to benefit from the treatment, it's necessary to replace their existing blood cells with their own blood cells, except those that have this editing.
(04:33):
And so that involves a bone marrow transplant. They have to be treated with something called busulfan, which is involved in chemotherapy. And that basically eliminates their existing blood cells. And then they are given their own cells back with the edit. And they're in the hospital typically for four to six weeks to be monitored to make sure that everything goes well. And if they need any supportive care to get the supportive care and after four to six weeks after their cells have engrafted, then they can go home and go on with their lives.
Theresa Brady (05:03):
Despite the rigorous ordeal, Casgevy is a one time treatment with a potential for lifetime benefit. The ex-vivo procedure is viewed as perhaps a first generation application of CRISPR technology. Our guests today are working on the next generation, which is in vivo applications.
John Leonard (05:21):
I'm John Leonard, and I'm the CEO of Intellia Therapeutics.
Christos Kyratsous (05:25):
I'm Christos Kyratsous. I'm a Senior Vice President for Research at Regeneron Pharmaceuticals.
Theresa Brady (05:30):
Intellia and Regeneron have been collaborating since 2016. Both companies work on genetics, so the partnership was a no-brainer. Intellia's CEO, John Leonard, explains why.
John Leonard (05:42):
We've collaborated with Regeneron since 2016, which has been a wonderful relationship, certainly for us, and we also believe for them. Regeneron is interested in gene based medicine and have had a very substantial effort to identify novel genetic targets, which is exactly what we're looking for. So they've been able to bring certain technologies that augment and complement our own.
Theresa Brady (06:09):
For Regeneron, Intellia's platform technology, in addition to its focus on gene editing, were clear draws for the company.
Christos Kyratsous (06:16):
About 10 years ago or so, Intellia was founded and they were one of the pioneers in the field of genome editing. And they were not only trying to understand how to apply genome editing in cells, but they were also, it was very evident from the first interactions with Intellia, they were trying to create a platform and they can apply this knowledge to as many areas of biology and as many versions of the technology as possible to tackle different disease areas.
Theresa Brady (06:43):
The two programs the companies are collaborating on involve editing the genome within the body. If successful, it will mark yet another milestone for CRISPR technology. Intellia's John Leonard explains that both ex vivo and in vivo each have their place in the drive to help patients.
John Leonard (07:01):
When one approaches using CRISPR as an editing format for therapeutic purposes, the first decision is whether or not those cells can be taken outside the body and manipulated and then put back in. That would be ex vivo gene editing. Or whether one needs to take the therapy into the body and edit those cells where they reside in whatever tissue where the genetic disease may have its origin.
(07:26):
At Intellia, we try to target both of those different approaches. Ex vivo gene editing is typically done for cells that are of the lymphocytic type of cells that grow in the bone marrow, whether they make red blood cells or cells of the immune system. Those cells are easily taken out, manipulated, and then put back in and can be used to treat patients with cancer or blood disorders, et cetera. But a lot of the difficulties with genetic disease reside in tissues that can't be taken outside the body.
(07:59):
So, if one has cystic fibrosis, you need to go into the lung and modify those cells. If one has a liver disease, for example, can't take the liver out, you got to take the technology into the liver. The same thing is true for the brain and any number of tissues. So, an in vivo approach, where you take that CRISPR technology to the affected cells, absolutely critical to get the full benefit of what the technology can bring.
Theresa Brady (08:25):
The procedure for the in vivo treatment is surprisingly much less complicated than the ex vivo treatment described earlier.
John Leonard (08:32):
What we do is take the CRISPR Cas, introduce it with an IV formulation. So a patient will go to a clinic, sit there for a couple hours, the IV will run in, they'll have a dose of steroids and antihistamines the day before, and then they go home. And that's the extent of what they experience.
Theresa Brady (08:50):
Perhaps the most critical component of the in vivo gene editing is the delivery. How does CRISPR-Cas9 reach its intended target?
John Leonard (09:00):
There's the delivery tool, in our case, typically a lipid nanoparticle. And that has its own set of experiments that are done to make the material, show that goes to the cell that is the intended target and show that it behaves appropriately and safely when it gets there. That's a whole line of work that we've spent several years working on and we think perfecting.
Theresa Brady (09:21):
And what is a lipid nanoparticle or LNP?
John Leonard (09:25):
A lipid nanoparticle resembles, in many respects, a little fat globule, if you will. This is something that might be 80 to 100 nanometers big, so it's very small and can fit between cells. It's made up of a lot of cholesterol and other particular lipids that are fat molecules that give it certain characteristics to get into cells and be taken up by natural receptors that reside on the surface of those cells [inaudible 00:09:53] it's metabolized once it gets inside those cells.
Theresa Brady (09:55):
According to Christos, the LNP delivery tool helped determine which diseases the companies would target.
Christos Kyratsous (10:02):
In the early days of the collaboration with Intellia, we started thinking of how to best apply this in vivo gene editing applications and what disease areas to start prioritizing. The version of the tool, the genome editing tool, uh, that was available to us at the time was based on a lipid nanoparticle.
Theresa Brady (10:24):
LNPs tend to accumulate in the hepatocytes, which are the cells responsible for a variety of functions like carbohydrate, lipid, and protein metabolism, detoxification, and immune cell activation. Hepatocytes make up 80% of the liver's mass.
Christos Kyratsous (10:41):
You can think about it as a sphere that is surrounded by lipids, and that naturally goes into hepatocytes, into the cells that constitute the liver in an organism. And this is the vehicle that is carrying all the components that are required to perform genome editing in vivo. So once you have your lipid nanoparticles with all the components inside, you can infuse it, you can inject that into an animal or into a human being. And this particle is going to go into hepatocytes and it's going to perform the genome editing.
(11:13):
So just because of where this sphere goes, where this delivery vehicle goes, we prioritize diseases and genes that are expressed in hepatocytes, are expressed in the liver. So we started prioritizing diseases that are primarily caused by genes that are expressed in hepatocytes. And one of them, was TTR. It's a form of amyloidosis that is affecting either the cardiomyocytes or nerves, but the protein that is causing this is almost exclusively expressed in the liver.
(11:47):
It's a disease that is genetically defined, okay. So we know that when there's a mutation in that gene, that is the cause of the disease. So again, this makes the link between the genome and the disease, there's a direct link between the two. And we also knew that in both preclinical models and also, uh, there was some evidence in humans, that when you disrupt expression of this gene and you stopped expressing this gene, there are no immediate bad consequences.
Theresa Brady (12:16):
TTR mutations are responsible for two main types of diseases. One that affects the nervous system and one that leads to cardiomyopathy, which is a disease of the heart muscle. Right now, the treatment options are supportive care to manage symptoms, medications to stabilize or slow disease progression, and in some cases, liver transplantation to replace the defective TTR producing liver cells with healthy ones. Patients suffering from these diseases see hope in the Intellia Regeneron program, which is in Phase III clinical trials using CRISPR-Cas9 in vivo to suppress the TTR mutation.
Christos Kyratsous (12:57):
What we've seen in the TTR trial so far is when we deliver the CRISPR-Cas9 components against TTR in humans, we see a very impressive extent and duration of stopping expression of TTR. What do we see in humans in the trials that we've run so far is that you can suppress the levels of TTR expression in the body by about 90%. And we see this response to stay for way more than a year so far, which is exactly what you expect. That's exactly the promise of genome editing. It's a one and done therapy.
(13:33):
It's a permanent manipulation you are doing in your genome. So you are expecting the response to be durable, to stay there because it's going to be propagated with your DNA. It's going to stay with you for the rest of your life, which is the promise of one and done therapies.
Theresa Brady (13:54):
After the break, we'll be right back. A BIO membership can take you and your company to the next level. Listen to what KaloCyte's CEO, Elaine Haynes, had to say at a recent BIO hosted event.
Elaine Haynes (14:22):
The advocacy that BIO does on behalf of our industry is critical to make sure that the drugs that my company is developing now, when they get to market, will have the proper construct for them to be successful.
Theresa Brady (14:37):
Visit bio.org/join to learn more. Both Christos and John agree that the major challenge that remains for in vivo gene editing is the delivery tool. Christos described how far we've come and what we're still up against.
Christos Kyratsous (15:05):
So one of the major challenges that remains in the field is delivery. So you can basically go into your DNA and you can do very, very specific and precise changes to your genetic code, okay, which is something that we couldn't even dream about (laughs) 10 years ago. So this is, this is pretty amazing. But despite of these phenomenal evolution of the enzymes, I think one of the major limitations in the field is where we can take and direct these enzymes inside the body.
(15:37):
The lipid nanoparticles are amazing tools, okay, and they allow for very, very efficient delivery of these tools into hepatocytes. So you can do all of these changes in the liver. But unfortunately, not all of diseases are caused by things that are expressed in the liver. There are many, many diseases that are caused by things that are expressed in the liver. And there are many, many, many things you can do in the liver, but unfortunately, there are many other tissues in the body that would benefit from getting access to these editing enzymes. And there are many genes that eventually you want to manipulate in other tissues in the body.
Theresa Brady (16:11):
John also stresses that while scientists are making tremendous progress with this technology, there are still some limitations, delivery being one of them.
John Leonard (16:20):
CRISPR-Cas9 is a new therapeutic modality. And so, taking something from how it exists in nature and bending it into a therapeutic requires some time and effort to go with it. We've had a lot of success making sure that we can come up with these processes to sort out where the guide goes and where it doesn't go and identify that across the entire genome. The other big part has been working out the delivery. It's one thing to deliver CRISPR Cas in a Petri dish, if you will. It's a much more challenging effort to deliver it to the liver or the brain or the lung.
(17:00):
And so, while we've certainly put a lot of effort into developing the gene editing technology, we also put a tremendous amount of effort into the delivery technology so that we can send it where we want it to go.
Theresa Brady (17:12):
Despite the challenges, the two companies are optimistic that what Christos describes as the liver's bio factory will open the door to treatments for multiple other diseases.
Christos Kyratsous (17:24):
During the course of our collaboration with Intellia, we also started thinking about other ways of manipulating the hepatocytes and try to make a difference for disease. And something that was very apparent to us very early on, of course, is that we knew that the liver hepatocytes are very, very good at expressing things. They are very, very good at producing proteins at fairly high levels and secreting them in circulation. So a lot of the proteins that we have circulating in our bloodstream are actually produced in the liver.
(17:54):
So we thought that the liver can become a very good, what we call biofactory. Something that can generate high levels of protein in hepatocytes and secrete them in circulation. So we started thinking about potential therapeutic applications of that. And our attention turned to diseases like hemophilia. We know exactly what are the genes that are not being expressed.
Theresa Brady (18:18):
Hemophilia is caused by mutations in the Factor IX gene. If it is missing, blood doesn't clot causing serious issues that could be life-threatening. Intellia and Regeneron are working on a delivery tool called Adeno Associated Viral Vector or AAV, which works with LMPs and carries the normal Factor IX gene to the exact location to insert it into the cut that was made with Cas9.
Christos Kyratsous (18:46):
So your lipid nanoparticle is going to get inside your hepatocyte and that's going to mediate the cut into your genome. Your genome is going to stay open waiting basically for the AAV to bring its genome inside the cell. And it's the AAV genome that's going to go and it's going to get inserted in that site. And you're going to basically get expression of your new function that you bring in with your AAV genome inside your hepatocyte.
Theresa Brady (19:10):
The concept has been tested in animals and the companies are now ready to bring it to the clinic.
Christos Kyratsous (19:15):
So we just started the clinical trial. We hope that we're going to be able to dose the first few patients later this year to see if this concept can apply in humans. So that will provide a cure for hemophilia, hopefully, but it will also open the door to multiple other diseases that can benefit from that platform. This will provide the proof that this biofactory concept for the liver is actually something that is doable. So we can start applying that for many other genes that we can insert in the exact same location in the DNA of hepatocytes to express other things that we want to express, other therapeutic proteins that we want to express from the liver. So that opens the door to many other applications.
Theresa Brady (20:05):
I want to thank both John and Christos for helping us understand the complex yet exciting frontier in genetic editing within the body and what it takes to bring safe and effective medicines to the market. Their dedication is obvious. I'm Theresa Brady and I produced this episode with help from Lynn Finnerty and Courtney Gastineau. It was engineered and mixed by Jay Goodman with theme music created by Luke Smith and Sam Brady. Make sure to subscribe, rate, and or review this podcast and follow us on X, formerly Twitter, Facebook, and Instagram @iambiotech. And subscribe to Good Day BIO at bio.org/goodday.