(bright music) - Welcome to "Stanford Medcast," the podcast from Stanford CME that brings you the latest insights from the world's leading physicians and scientists.

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I am your host, Dr.

Ruth Adewuya.

Joining me today is Dr.

Matthew Porteus, who is a physician scientist and a global leader in field of gene editing and STEM biology.

He's currently the Sutardja Chuk professor of definitive and curative medicine and professor of pediatrics at Stanford University School of Medicine.

A pioneer in the field, Dr.

Porteus was the first to demonstrate the feasibility of precise genome editing in human cells using engineered nucleuses, laying the foundation for therapeutic gene correction.

His research focuses on developing curative therapies for genetic diseases, particularly sickle cell disease and other blood disorders by editing hematopoetic stem cells using CRISPR-based technologies.

He has played a central role in translating genome editing from the lab to the clinic, and his team continues to lead early phase clinical trials designed to evaluate the safety, efficacy, and scalability of these groundbreaking approaches.

Dr.

Porteus, thank you so much for chatting with me on the podcast today.

- Thank you, Ruth.

Really glad to be here.

- For listeners who may not be deeply familiar with the science, could you walk us through how CRISPR works, what it is, how it edits genes, and why is it considered to be such a breakthrough in molecular science?

- I'm gonna even step back a bit before CRISPR.

As you're going through medical training, we recognize that for certain diseases, if one could just change a nucleotide in the DNA of a cell or change the DNA sequence precisely, that you could address many diseases.

In the early 2000s, as people, including myself started to figure out ways of doing what we now call gene editing in cells.

The tools we had at the time were tools called zinc finger nucleases and TAL effector nucleases.

The way they worked is that you design a nuclease, a protein that makes a break in the DNA.

So it recognizes exactly where you want in the DNA.

It makes a break, and then that triggers the cell to repair the break.

By allowing the break to repair on its own, you can create new mutations at the site of the break, and we'll get into why that's important.

Or if you provide what we call a donor piece of DNA, the cell will use, the homologous recombination machinery to make a copy of the undamaged donor and paste it over the break to fix the break.

By designing the donor DNA in the right way, we can now introduce those exact changes to the DNA we want.

So this was all going on in the late 1990s, early 2000s, but the tools were hard to use.

What CRISPR did when it was discovered that you could reprogram it to make a break at a sequence very easily, and then when it was shown that this bacterial system worked very well in human cells, it totally changed the field.

Now, instead of having to spend several years to make a specialized protein, you could spend several days making a CRISPR nuclease.

The way the CRISPR system works is it has two parts to it.

It has a protein part called Cas9.

That is the scissors that's gonna cut the DNA.

And then it has an RNA part that gets abound by the Cas9 protein, and it's the sequence of the RNA that guides the molecular scissors to the right site in the genome to cut the DNA.

It's this very elegant two-part system where the Cas9 is used all the time, and by just changing 20 nucleotides in the RNA, you now can move the scissors to different parts of the genome.

- It sounds like what makes CRISPR revolutionary is its precision, flexibility, and accessibility.

And what you've said has set the stage for everything else that we will be discussing because it's really reshaping our ability to intervene at the root cost of disease.

- That's right.

Genome editing is a process of changing the DNA of a cell in a precise manner.

CRISPR is a tool to enable us to do that, but CRISPR is not genome editing.

And we'll get into maybe a little later that there are other different genome editing tools.

So you have a class and a tool.

- Yes, and we'll certainly talk more about that later, but one of the things that I also wanted to start our conversation with is to center the impact of this work because it becomes clearest when we move from talking about molecules and genes and all of that, and we move to people.

How has your experience as a clinician informed your approach to designing and translating gene editing therapies for real world use?

- I'll start with my personal story.

I was an MD PhD student here at Stanford, and it was on my clinical rotations in my third and fourth years of medical school that I met and took care of a young woman with sickle cell disease who came into the emergency room with pain in her bones, which is a common manifestation of the disease.

For the most part, the treatment of anyone who has sickle cell disease who goes into what we call a pain crisis is depending on the severity of the pain.

In its most severe cases, they're admitted to the hospital, they're given hydration, and they're given opiate pain medicine, and you'd wait for that pain crisis to resolve on its own.

What was striking to me and to many others is that what we were doing clinically to treat the pain crisis caused by the variation that causes sickle cell disease compared to what we knew about it from a molecular biology and genetics perspective.

One could argue the disease that has taught us the most about how genetics interface with human health.

It has always been a pioneer in our understanding of that really complicated and industry relationship that permeates all of medicine.

Yet we had no good therapies based on that knowledge.

I came out of medical school idealistic.

We need to bridge the gap between the knowledge of genetics and developing genetic therapies, highly precise genetic therapies to address the genetic basis of the disease.

- It's incredibly powerful to hear how a patient's experience can directly shape scientific priorities and a reminder of how important it is to ground research in the real world realities of care and to stay connected to what patients are truly facing.

In what ways is genome editing enabling a more personalized approach to care, especially for patients with rare or treatment resistant genetic conditions?

- That is a problem that we're still working on.

Sickle cell disease is unique among serious genetic diseases in that every patient has the same, and I use variant not mutation because if you have one copy of the sickle cell gene and one copy of the A gene, so your SA, you're actually resistant to malaria.

So it's beneficial to have one S and one A if you get malaria.

It is only detrimental if you get two S genes.

So I don't like to think of it as good or bad.

It's all contextual.

But every person with sickle cell disease has that same S gene, which means that if you designed an approach for one patient, you could treat them all.

Most genetic diseases don't have that feature.

Instead, there might be hotspots that cause the disease, but there are mutations that cause the genetic disease that are scattered throughout the genome.

A CRISPR system that could treat a one size fits all mutation for any given genetic disease.

My lab and other labs have worked on that.

It's a specific genetic therapy for one disease.

What was exciting two weeks ago was the announcement that was designed to correct that patient's mutation and only that patient's mutation, and that was so super personalized.

Six months in multimillion dollars of work, they only worked for that one patient and that boy, who's been publicly described as baby KJ, had a super severe metabolic disease of the liver, and now his disease is significantly less severe and he's growing and is doing so much better.

The question then is, in the future, can we get to a place where everyone will have their personalized CRISPR system or is that just a mode of drug development that is a bridge too far and instead we're gonna have to go back to one system that could treat one disease?

- That's such a dramatic departure from how we've historically managed chronic conditions.

- Yeah.

- I'm also thinking about the scalability of this and how all of that would work.

How close are we to CRISPR based therapies becoming part of mainstream treatment?

- To the first part of the question, maybe I'm not idealistic enough to think that personalized CRISPR therapies will become common.

That's really hard to get my head around.

I feel like it might work for a handful or more patients, but you know what?

I might be proven wrong and in 10 years, I might have to eat my words, which is fine.

In terms of sickle cell disease, we don't really have that issue because every patient has the same variant.

So you don't have to design a personalized system.

In December of 2023, two gene therapies were approved for the treatment of sickle cell disease.

One developed and sponsored by a biotech company called bluebird bio was based on using a virus to deliver a copy of the beta globin gene into hematopoietic stem cells, the cells that give rise to red blood cells so that you now create a cell that has the S gene and NA gene.

They treated in the range of 40 to 60 patients.

They showed that those who got the therapy, their amount of pain, the frequency of their pain crisis, the amount of pain was significantly better.

And that led to its approval.

The trade name for that drug is LYFGENIA.

Casgevy is the CRISPR drug that was approved in the US by the FDA on the exact same day.

The way Casgevy works, it is known that counteracting the S protein is something called hemoglobin F, the fetal hemoglobin that we have before we're born.

If you have S and F, the F can counteract the S.

What Casgevy does is, so before we're born, we have lots of F in our red blood cells.

And after we're born, our genetics puts a break on F to allow the adult hemoglobin to turn on, which in this case is S.

What years of genetic research and then molecular biology research and mouse studies showed is that a protein called BCL11A is one of the major breaks on F.

If you inhibit the break, you can release F.

What Casgevy does is it inhibits BCL11A from being turned on in developing red blood cells.

And so now you get F to counteract the S.

Now you'll notice that they're indirect workarounds to address the SS.

What my lab has done is to use CRISPR-based genome editing to directly change the S to A.

Now instead of having SS, we will convert the S to A.

You only need to convert one S to A to create sickle cell trait.

That's what we're trying to do 'cause we think that is the true endpoint for gene editing for sickle cell disease.

- It sounds like there have been some real landmark moments both in terms of new approvals and the shift to frontline therapies and your lab is also contributing to the next phase of this work.

When I think about what comes next, especially as these therapies move from development into real world use, two things immediately come to mind.

Access and safety.

Safety in particular becomes even more critical when we're talking about introducing genomic changes.

From your perspective, what are some of the most significant challenges in translating gene editing into clinical practice?

- For sickle cell disease and for other genetic diseases of the blood, the processes goes through what we call an autologous bone marrow transplant.

The patient is hooked up to a machine apheresis device.

We have to get their hematopoietic stem cells or blood stem cells out.

You can spin out the nucleated cells, and then that goes into a bag.

Then the cells get either genome edited or lentiviral engineered.

Then if that product of cells, which is several hundred million if not a billion cells, passes all the criteria, hasn't gotten contaminated, it's then ready to be released.

Patient has to come back in and get chemotherapy to ablate all of their endogenous hematopoietic stem cells to create space for the new stem cells, and then they get infused.

Now, that chemotherapy treatment using a drug called busulfan causes mucositis, it can cause long-term issues, infertility, it causes your blood counts to be low for several weeks or longer.

So you're at risk of infections, while the new cells find their homes and start making blood cells.

The first hard thing was getting the efficiency of the genetic engineering high enough in the cells you need without killing the cells.

You have to keep the cells healthy so that they will engraft and make new blood cells.

Then the next part is how do you incorporate that into a very complicated process?

In the long term, we would of course like to get rid of that chemotherapy for the conditioning.

We'd like to make the mobilization of the stem cells easier on some of the bigger issues around genome editing.

I heard a social scientist describe a dichotomy between perfection and perfectability.

We're always shooting for perfectability.

We have a north star to get to perfection, but we almost never get there, but we have to have that process that we can always do better.

These are some of the areas where we'll do better in the future.

Stanford is leading the charge in some of those areas, which is really exciting to have my colleagues be doing that.

- How much of a concern are things like off target effects or insertion deletion errors when you're thinking about clinical applications of gene editing?

- We are always concerned.

Do they make breaks where we don't want?

And when 10 years ago, when the CRISPR-Cas9 system was described, it was like, is this gonna be a problem?

It turns out this system is remarkably specific.

We didn't know it at the time.

One of the things you have to do is you have to show to the FDA that you have assessed how specific your process is.

And often, you can find no evidence of off targets.

It may mean they're not there, but it also may mean that you just can't find them.

When Casgevy was approved, they had a scientific advisory board spending the day to advise the FDA.

And most of the day was spent on have they demonstrate the specificity to a degree we should have confidence.

And the advisory board was unanimous in saying that the specificity had been demonstrated and the risk benefit entirely favored that this should be approved.

Now, that's just an advice to the FDA.

They ended up following that advice, but that's true.

We, meaning the entire field, spends a lot of time on making sure that the process is specific, but we've gotten to a point where I will even challenge my sequencing colleagues that if I give them two samples, I don't think they could figure out which one was edited and which one wasn't based on off-target effects.

We have to remember two things.

One is that the chemotherapy we give for the conditioning is far more genotoxic than any CRISPR editing.

The other thing to remember is our genomes in our cells acquire mutations every day of life.

I like bacon.

We know bacon has chemicals in it that damage our DNA.

We breathe pollution that damage our DNA.

Actually, just cells living where they create reactive oxygen species damages the DNA.

So there's no such thing as a cell that doesn't get damaged DNA and acquire changes.

Again, it's putting this all in context, how severe the disease is, what's going on in the background, can you detect it, and putting that equation together.

- That's really helpful context.

I imagine that when we're talking about applying these therapies to children, the bar is even higher, both ethically and clinically.

How do you navigate the balance between therapeutic potential and the unique ethical and regulatory complexities that come with treating pediatric populations?

- We and others could have hours of conversations, but the general framework is that if a disease is so lethal that people don't even reach adulthood, then of course, getting consent from a parent to investigate a therapy is ethically justified.

If it's a disease that's severe, but people reach adulthood, then the clinical trial has to start in adults for ethical reasons.

It's only after you've done a few adults that then you can move to adolescents.

Actually, both LYFGENIA and Casgevy are approved for the age of 12 and above.

What both companies are doing now is running the clinical trial in younger people to expand who can get it, who would be approved to get it.

Now, I will say for a disease like sickle cell disease and others, but sickle cell disease is a great example, it's a progressively destructive disease.

Even a healthy 23-year-old with sickle cell disease still has organ damage that a five-year-old wouldn't have.

This is a disease that in the long term, I think we wanna treat in early childhood before that inevitable destruction occurs.

- There seems to be a really thoughtful multidisciplinary approach to involving children not just in treatment, but in the broader process including clinical trials, and yet even as enthusiasm for these technologies grows, especially in areas like sickle cell disease, broader adoption still seems to be limited.

What's continuing to hold that adoption back?

Is it the complexity of the therapy itself, the infrastructure that is required to deliver it or something else?

- Treatment centers like Stanford's that have that capacity, that expertise, the first delay in getting this rolled out was getting treatment centers qualified to be able to administer this commercial therapy.

And I can tell you, it's very complicated.

Then patients have to be interested.

And to fit the eligibility criteria, they have to decide with their physicians and their family whether this is the best approach for them.

Once all that's happened, then it's a between six to nine months, maybe even longer process between I wanna get this and actually getting it.

The approval in December of 2023, it wasn't like there was a million pills on the shelf ready to give to patients.

It's not surprising that it's taken a little while for it to roll out.

We're seeing increasing number of patients coming into the queue and getting increasing number of treatment centers up and running.

Now, what the cap will be on that remains to be seen.

We're still very much in the build out phase.

I'm a believer that there are enough people with severe sickle cell disease that we need three or four or even five different products on the market to meet demand because these are complicated therapies.

We can argue about, is that better than one or that better?

But they're all falling into this really transformational approach to patients.

Third patient treated is a man named Jimi Olaghere from Georgia.

And listening to him talk about how it's changed his life is spectacular.

And I'll just highlight a couple points that I've heard him say.

One is that he used to think he was allergic to snow because every time he would go out into the snow, he'd have a crisis because that's known in people with sickle cell disease.

After his therapy, it snowed in Atlanta, which it occasionally does, and of course, the city shuts down.

He went on and played in the snow with his kids and realized he wasn't allergic to snow because he no longer had sickle cell disease.

The other great thing is that last summer, he was part of a fundraising educational effort that resulted in him climbing Mount Kilimanjaro and he believes he's the first person with sickle cell disease ever to climb Mount Kilimanjaro because at 21,000 feet, the low oxygen's not so good.

Those are the life-changing stories.

Many other patients have been very public about their stories and how they had put their life on hold, they weren't sure where their future was.

They get the therapy, and now they're back at it a hundred percent, fully optimistic about their future and onwards.

- These are such powerful stories.

Thank you for sharing them.

They really speak to what keeps people like you energized and committed to this work and to the hope of expanding access to these technologies.

You touched on this earlier, but one of the major challenges is cost.

These therapies hold incredible promise, but they come with a high price tag.

The cost of these technologies are probably upwards of a million or so.

- It's an interesting debate, and I'm gonna give a slightly different perspective.

The list price for Casgevy is around $2 million.

List price for LYFGENIA is $3 million.

And you're shaking your head and you're going, "That is way too expensive," and it is.

It is clearly a barrier, and what that means is that one of the barriers to the uptake is finding payers who are willing to pay that price.

Several of us have argued that actually, it's a bargain.

When you think about what the impact this disease has on people's lives, and when you hear stories like Jimi's and others about how they're now able to hold jobs, they're now able to pursue their careers, now I think about children who I've taken care of where the parents, often the mom, have to change their entire career trajectory because they never know what day they can't show up for work 'cause they have to take care of their kid who's in pain.

I think the direct and indirect costs and lifetime benefits, this is a bargain.

Now, that does not mean that the sticker shock price is not causing people to pause.

That does not mean that we shouldn't find ways to make it cheaper.

I just don't want it get out there.

This is great, but it's too expensive and it's not worth it.

I wanna say, "This is great.

It is expensive, it is worth it even at this price, but let's figure out how to make it cheaper." - I really appreciate the perspective you're offering and I agree the framework makes a lot of sense, but I think it's a yes and situation.

The context is compelling, but how does it actually translate into real world access for the people who need it most?

Because if access isn't built in, then even the most promising frameworks ultimately fall short.

- Exactly.

I don't wanna get into huge political discussions, but this is why funding for Medicaid and Medicare are so important because no individual can pay for this out of their pocket.

This is paid for either through their own private health insurance, through Medicaid, or through Medicare.

When there are threats to those systems, then access to payment for these therapies is significantly burdened.

In the meantime, that's our job in academia and biotech is to figure out how to bring that cost down so the upfront burden is lower.

- Absolutely, I couldn't agree more.

That's such a valuable perspective and one I honestly hadn't considered before.

It's exactly why I love having these conversations.

They expand how we think.

As we begin to wrap up, I'm curious, for clinicians who don't work directly in gene therapy, what practical implications should they be aware of as these treatments start to enter broader clinical use?

- I'm just one person with a poor crystal ball.

Take it for what it's worth.

There's a couple things that come to mind.

One is that right now, the gene therapy, gene editing, and the entire biotech drug development space is very much in a winter.

There was tremendous enthusiasm in 2019, 2020, and since COVID, I don't think it had anything to do with COVID honestly.

The enthusiasm has swung too far in the other direction.

My word is that it will come back.

That gene editing, gene therapies, they work.

Just came back from the annual meeting for the American Society of Gene and Cell Therapy and the science is amazing.

It just keeps working.

It keeps getting better.

People are doing cooler and cooler things.

So we'll get there.

That being said, most of these therapies and even sickle cell disease falls into this category, are directed at rare diseases.

At some point, the ability to use gene editing, gene therapy to treat a common disease is going to happen.

That's when this modality is going to change medicine.

When instead of having to take a pill every day of your life, a one-time therapy that will treat your disease for the rest of your life, that's our goal.

That's what we're trying to do at Stanford.

Our Center for Definitive and Curative Medicine is rock the boat on how we think about treating not just rare genetic diseases, but more common diseases that might affect all of us with one and done type therapies.

Are we there yet?

No.

But are we there in mice?

We are there in mice.

Now, how do we get from mice to humans?

And I think for those out there listening in, thank you for listening.

That's what you wanna start listening about.

When do you hear about something that isn't just for rare diseases?

Now, as a pediatrician, I'm all in on rare genetic diseases.

Those patients, those families mean everything to us and many of my colleagues, but we also need to get to more common diseases as well.

- Thank you so much for walking us through both the complexity and the promise of CRISPR-based therapies.

It's clear that moving from bench to bedside isn't just about innovation.

It's about translating science into meaningful patient-centered change.

As gene editing continues to shift from novel to standard practice, your insights will be incredibly valuable to both clinicians and patients.

Thanks again for joining us.

- Thank you again, Ruth.

- This episode was brought to you by Stanford CME.

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