Over the weekend (on Thursday, May 15), it was announced that doctors at the Children's Hospital of Philadelphia used a personalized CRISPR therapy to treat KJ Muldoon, a baby with a rare genetic condition that causes ammonia to build up in the body. For those who haven't seen the news, can you explain what happened with KJ and why it's such an important milestone for gene editing writ large?

KJ was born with a very, very rare disorder. When we say rare, we're talking about maybe hundreds of people across the entire planet who have this disease, so it's very different from the normal drug development that we think about. This disease is normally fatal unless there's a liver transplant, which of course is very challenging to do, and it's hard to find a liver for someone who's less than one year old. About two-thirds of these patients die before they reach their first birthday, so it's extremely devastating.

What happened here, which has been a really exciting topic of conversation but had never really happened practically for CRISPR, is that people rapidly developed a new therapy, a new version of gene editing that was able to correct this genetic disorder. And they were able to do that in about six months. Especially in the news nowadays, we hear about the challenges of drug development and that it might take a decade or two decades to make a new drug. Through this incredible tour de force, they were able to compress that to about half of a year.

That was administered earlier this year. We're starting to see the results, and it looks like there are no bad effects, which is important. Of course, safety of the drug is the first thing that needs to happen. But the early signs look good that this was successful and was able to treat and correct the genetic problem that KJ had, specifically in the cells of KJ's liver.

It's pretty incredible. From a process point of view, for someone like KJ, how does that get jumpstarted? Who is the person who at some point said, "Maybe we should try to make a personalized CRISPR-based therapy, and let's try to get this done in six months"? Was it the doctors at CHOP in Philly? Was it someone else? Was it part of a clinical trial that he got enrolled in? How does that even come together in the first place for someone in KJ's situation?

A lot of this often starts with the families themselves, of course, getting the diagnosis. And then there's this collaboration and huge group of people. Here in particular, there were so many groups that jumped on the train and were happy to help, many scientists who, from the stories, were working day in and day out trying to get this done in the very limited window of time that they had.

I think you're starting to see this more general movement and excitement around what we call N-of-one treatments, where you're really building bespoke therapies for patients. But in this case, it really was a village of people that came together with different expertise, including, of course, the physicians, the labs that develop the gene editing reagents, and a lot of collaborators in other groups that helped out with very specific components. Of course, you have to make the drugs, so there were groups helping out there as well. But a lot of it starts with the patients themselves, and in this case the parents, families, and people who are directly impacted and really want to find something urgently.

If we think about the timeline here, call it six months start to finish, I assume that's warp speed. Is there a world we're approaching where that becomes commonplace? Or is this a true outlier, given the amount of resources, time, attention, and care that were seemingly given to KJ? Where are we headed on speed of implementation with CRISPR today?

Zooming out, the real innovation with CRISPR was always that it's a programmable medicine. You start with something that can edit the DNA, but the way you target it to a certain gene or diseased sequence in the genome is just by changing this little sequence of RNA. I think that's really the underpinning of this.

It took about a decade to get from discovery to the first approval of CRISPR, which was the drug Casgevy. But the important concept here is that once you do that first one, once you actually start to understand how the tool works and you've de-risked the platform, it's much, much more rapid to develop the second and third therapy. What we're seeing now is that for particular categories of diseases, where you have some other program that's worked, it's actually quite straightforward. And really the limitation is now becoming how we think about trial design and regulatory strategy, to be able to recognize that this is programmable and predictable in how it's going to behave and work.

I don't want to diminish the work of all the researchers, and this definitely was rapid. But I think this is part of a bigger trend: the technology is now mature enough that you can think about how to do this more systematically, and potentially even make it shorter than six months as we get better and better at this.

What are the blockers in place today, whether that's the FDA or other agencies, preventing this technology from more widespread use, or maybe even a world where we have thousands of people saved in a given year by some personalized gene editing therapy?

The FDA and other international regulatory bodies are usually very cautious about new types of interventions, with good reason. Many of these programs do pose some kind of safety risk, so it makes sense to be cautious. But where we're at now is that you're hearing a lot of people talk about the concept of a platform approval, as opposed to a program approval, which is traditionally how things are done. Our regulatory agencies are very well versed in things like small molecules, pills that you might take, or antibodies, which of course have been really, really productive. But there still hasn't been full recognition of how distinct this type of therapy is, something that is really reprogrammable and where you can predict how it's going to behave before you actually use it.

This concept of a platform approval is really where I think the field, whether it's the FDA or others, will move to. I think that's what will ultimately develop out of this. But basically what you're saying is the FDA can approve every single component of a therapy except for that tiny little change that you're making. In KJ's case, you have a very particular type of gene editor, and you have an LNP going to the liver, which is very similar technology to what we use for mRNA vaccines. All those components can stay exactly the same, and all you're asking the FDA to approve would be the new sequence that you're targeting.

That can become not just a much faster process, but also much more amenable to treating it as a data science problem, where you're able to predict in silico, in the computer, how that molecule is going to behave based on how it interacts with the genome. I think that's a really exciting area that you're seeing a lot of groups start to push on. This case with KJ is a really important success story, because a lot of these N-of-one therapies haven't worked. This is an example where it can, and we don't need to go through a 10-year process to treat a disease where patients are dying before they turn one.

The ones that haven't worked, why is that? Have they been CRISPR-based, or are they other therapies that have failed?

An important factor of this particular disease is that the cells that need to be corrected are in the liver. One of the big challenges of CRISPR and gene editing has been how you actually get the gene editing component to the right cells in the body. You can imagine many diseases: some are caused by the liver, some by the kidney, some by the brain. You want some way to get the editing reagent to those particular cell types.

For the liver, a lot of the legwork had been done previously by developing these LNP technologies, from companies like Intellia, CRISPR Therapeutics, or Beam that have programs where they're treating liver disease already. So there really wasn't much innovation and iteration that needed to happen on the delivery side of things. That's one of the reasons this was so much more successful: that component was already checked. And honestly, that's probably the biggest risk of any of these.

For other cells in the body beyond the liver, you have to use other delivery technologies. A main one that people use is called AAV. This is basically a virus that we've domesticated to be able to target different cells in the body. We can take out the viral genome and put in whatever we want. Those can work well for the muscle or for the heart, but they're much more challenging to manufacture, and they're earlier in terms of the clinical de-risking that's happened so far.

I think with time that'll develop. But this really does demonstrate that once you prove it out with a particular type of editing, a particular flavor of CRISPR, and a particular type of cell in the body, once you have de-risked that, it's quite straightforward to move on to the second, third, fourth, and hopefully thousandth iteration.

What are the top one or two next candidates from your point of view, whether body parts or organs, where we're far enough along in our discovery and understanding, like with the liver, that they could make great candidates for the next iteration of one-off personalized gene therapy?

I think the brain really is the holy grail for this. There's been a tremendous amount of progress on getting the AAVs that I mentioned to go into the brain and function. The liver regenerates. It's a pretty, what's called, durable organ. You don't want to do anything wrong once you start editing the brain.

But I think that really is where there's so much untapped opportunity, in terms of diseases where we know the exact cause from a genetic standpoint. We know that if we change this base, this part of the DNA, into a different part of DNA, it'll cure the disease. And it really does come down to those delivery challenges. Some of these diseases are so debilitating, and I think that's really where things will develop over the next five or 10 years.

Of course, we're focused on infant disorders here with KJ, but we have to think about health span and how people live the last years of their lives as well. So many of those things are disorders of the brain, neurodegeneration, where your brain starts to decay, and even if you're kept alive, the quality of life is so much lower. That's really what I'm most excited about in the new developments to come.

The KJ news was incredibly powerful and feels like a seminal moment for the technology itself. I'm excited on a personal level, from afar, while you spend every single day working on this, to continue to see the advances here. Even though this is only an N of one, it seems like a really foundational piece of the puzzle. Hopefully in the next three, four, or five years we'll have even more of these, perhaps in other areas like the brain, as we mentioned. Thanks so much for joining, Lucas. It's great to have you.

Yeah, thanks a lot.