CRISPR Just Saved a Baby’s Life… Millions Could Follow

It's August of 2024, and a beautiful newborn baby in Philadelphia has just been diagnosed with a rare liver disease.

Caused by a genetic mutation, this disease is incredibly deadly, killing around half of its patients in infancy.

And the only cure is a liver transplant… something this baby, nicknamed KJ, is too little to get.

A team of scientists has a more ambitious plan.

They are racing against the clock to edit KJ’s DNA inside of his own body — something that has never been achieved before.

Spoiler alert: they did it.

At time of filming, KJ is doing great, thanks to a treatment so advanced it sounded to his own parents like science fiction.

But it is a reality now thanks to these scientists… and they hope that KJ will be the first of many to benefit.

Here is how they did it.

[♪INTRO] Now, KJ is not the first person ever to receive gene editing therapy. Far from it.

Various approaches have been developed over the last few decades for more common diseases.

The history of gene editing in humans has also involved multiple ongoing ethical and technical challenges.

But KJ was the first to receive a personalized, in vivo gene editing drug.

In vivo means inside a living thing, as opposed to in vitro, which means in a test tube, petri dish, or insert lab paraphernalia here.

Meaning previously, gene editing in humans was largely done by removing their cells, treating them, and then putting them back into the body.

And personalized in this case means the therapy was tailor-made just for little KJ.

In other words, the research team engineered a microscopic fleet of custom gene editors to travel via IV infusion to the liver and literally modify the DNA inside the cells.

The idea is that this modification would correct a catastrophic typo in KJ’s DNA.

KJ’s father has been quoted as saying that the scientists’ explanation sounded like a futuristic sci-fi, out-of-this-world technology that he didn’t know anything about.

But who would know about this? Just the doctors who are doing it.

It’s new.

What he did know though was that KJ’s life almost certainly depended on it.

Helping this baby has been an amazing feat that offers hope that he will live a long, healthy life.

But even better, it could also pave the way to treat all kinds of other, often fatal, and crucially super-rare diseases.

Let’s get into the saving KJ play-by-play.

Shortly after he was born, doctors diagnosed KJ with carbamoyl-phosphate synthetase 1, or CPS1, deficiency.

Researchers at the University of Pennsylvania and Children’s Hospital of Pennsylvania sprang into action immediately.

They had used similar approaches to try to help children in similar cases.

But they had learned valuable lessons, allowing them to complete the process faster than before.

They were hoping beyond hope that KJ would be the lucky first.

The team knew that every day would be crucial, and that they would have to execute their plan to perfection.

First, let’s get into the details of his diagnosis.

That CPS1 gene codes for an important liver enzyme.

KJ received a faulty version from each of his parents.

KJ and others with CPS1 deficiency have a misspelling in the DNA sequence of the gene.

This enzyme is involved in the first of five crucial steps in what’s called the urea cycle.

This is a series of biochemical reactions that convert waste ammonia in the blood into urea, allowing it to be excreted when you pee.

There are other urea cycle disorders in which another of the five steps is disrupted by a different gene mutation.

The misspelling causes the liver cells to produce a broken enzyme.

All humans produce a small amount of ammonia, mostly as a byproduct of protein metabolism.

In patients with CPS1 deficiency, ammonia builds up in the brain when they consume protein.

KJ had to start a grueling regimen immediately after birth, including taking an intensive amount of drugs.

He also had to eat a restricted amount of protein in his diet just to stay alive.

And this is bad for a baby! Babies need protein.

The only cure for the disease is a liver transplant.

But CPS1 deficiency is so dangerous that not all patients survive long enough to get one.

That’s because there are a lot of risks and challenges to giving liver transplants to tiny infants.

One of those challenges is that they just plain aren’t big enough.

KJ’s disorder is considered ultra-rare.

It’s one of thousands of different so-called rare diseases, each of which occurs in very, very few people, and most of which are caused by a genetic error.

But if you add all these rare diseases together, millions of people have one of those diseases.

CPS1 deficiency is thought to affect fewer than one in a million people.

To be born with such an improbable mutation is largely a result of bad luck.

But KJ’s parents, doctors, and personalized research team would do everything in their power to defy the likely death sentence.

The clock started ticking right when he was born, and the tenacious researchers were ready to move.

Right away, they identified a specific CPS1 problem variant in KJ’s DNA called Q335X, which came from the child’s father.

This specific variant causes liver cells to create a shortened version of the CPS1 enzyme.

However, if KJ had only had that one mutation, he would have been ok. CPS1 deficiency is a recessive disease, and requires both versions of the gene to be non-functional.

And the team found that the copy of CPS1 from the baby’s mom, denoted E714X, also leads to a shortened protein.

But Q335X had been associated with CPS1 deficiency in another newborn, so that was the one they chose to target.

The plan also involved creating what’s called a patient-specific cell line, which is a collection of cells with someone’s unique genetic sequence that can be studied.

It wasn’t safe enough to biopsy KJ’s liver cells, though.

Instead, the scientists synthesized and inserted specific DNA sequences from KJ’s genome into a different cell line, one that’s been grown and used in research since 1982.

The cells were ready to go by the time KJ was one month old.

Meanwhile, they also had to create a therapy customized to correct the specific mutation in KJ’s liver cells. But they were on top of that, too.

CRISPR-Cas9 technology is the world’s best-known type of gene editor.

The CRISPR component borrows bacterial machinery to find a specific DNA sequence.

Cas9 is an editor protein involved in snipping and changing that sequence.

KJ’s treatment is similar to CRISPR-Cas9, but uses a different sequence finder and editor.

One piece of KJ’s treatment, the guide RNA, was engineered to find the right spot on chromosome 2, where the mutation was located.

Attached to the guide RNA would be an adenine base editor, which is a protein that edits the DNA strand at a specific site.

This editor rewrites only one letter, replacing an A — of the ATGC DNA alphabet — with a G.

For this reason, base editors like this one come with a much smaller risk of unintended consequences than traditional CRISPR-Cas9.

The ultimate objective is for this small edit to prompt the cell to fix the faulty gene so it starts to produce the CPS1 enzyme.

The team had the treatment formulated by the time the baby was 2 months old.

They dubbed this bespoke treatment k-abe in reference to KJ and the name of the editor.

It would then be encapsulated into extremely tiny lipid nanoparticles, which are tiny fatty blobs that act like a delivery vehicle for K-abe to get from the IV, through the body, and to the liver.

Another crucial step was to engineer mouse models for testing purposes — a task that began immediately after KJ’s diagnosis.

Just like the treatment, they had to be customized to KJ.

They took the same sequences they had used to create the custom cell lines and inserted them into mouse embryos.

By KJ’s third month, the patient-specific mice were also ready to go.

Despite his strict regimen, KJ was experiencing episodes of high ammonia, each one taking a toll on his little body and increasing the risk of irreversible neurological damage and death.

I know how this story ends and yet it is still stressing me out!

But you will have to wait a little longer, because we do need money to make the episodes, so it is time for a short break.

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In month four, it was time to meet with the FDA before applying for what’s called an Investigational New Drug application.

This is how researchers get approval to administer a new drug to a patient, even outside of a clinical trial.

In KJ’s case, the researchers requested an expanded version of this permission, which is sometimes known as compassionate use.

This meeting was when the researchers began getting the initial paperwork squared away.

By month five, the urgency had intensified even more.

At this point, baby KJ was even sicker and officially added to the liver transplant list.

But finally, in months five and six, it was time to test the full treatment.

One possible issue with gene editing is the potential for unintended germ-line edits, meaning edits that change the reproductive cells and would be passed down to KJ’s theoretical offspring.

There’s also the potential for off-target mutations that might affect the function of any given gene, including mutations that could contribute to developing cancer.

So the team did what they could to satisfy themselves that the risks of both were acceptably low.

It wasn’t zero, but when a life is on the line, a small amount of risk can be ok.

They also did a toxicology study in nonhuman primates and in the mice that they had engineered.

Neither the monkeys nor the mice showed signs of toxic effects, which led the scientists to conclude that there was a high enough chance that it wouldn’t be toxic to KJ either.

The team immediately submitted their expanded investigational application, and the FDA moved fast, knowing what was at stake.

One week later, the researchers had their approval in hand.

It was now the moment of truth.

KJ’s parents knew that the potential benefits of K-abe outweighed the risks, given his dire prognosis.

They gave the scientists the green light.

To prepare for treatment, KJ received immunosuppressive drugs to prevent antibodies from forming against k-abe.

Then he got an initial low dose to check for side effects.

And, great news, his body handled it without major hiccups.

Soon, KJ was doing better to the point that he could eat more protein without triggering dangerous ammonia levels.

He got two more infusions at months 8 and 9 and showed even more improvement.

K-abe isn’t a cure for CPS1 deficiency; it’s a treatment that seems to have greatly reduced the ammonia build-up in KJ’s blood.

He’s not totally out of the woods, and will require long-term monitoring, continued medication, and possibly additional doses of k-abe.

It was also too risky to biopsy his liver and sequence the DNA in the cells to conclusively confirm that the intended gene editing occurred.

But the improvement in his condition is pretty darn clear: something good definitely happened.

Which means that, after living his whole young life in a hospital, KJ got to go home. We love that for him.

Even more good news is that k-abe’s success shows that in vivo gene editing could be deployed to treat practically any genetic disease, like other liver disorders, blood disorders, and even cancers.

The personalization is a game changer for rare diseases.

Rare diseases have long been neglected because common diseases are prioritized for funding.

So that makes this leap even more remarkable.

Each type of super rare disease can be as rare as getting struck by lightning. But together, rare diseases affect millions of people.

by lightning. But together, rare diseases affect millions of people.

There are challenges to scaling the k-abe approach, including designing gene editors that can successfully edit the cells of different tissue types, like bone marrow, T-cells, and the brain.

But k-abe has been no small feat for humankind.

We’ve been to the moon, we’ve developed antibiotics and vaccines, and now, we’ve made lifesaving edits in a living child to his literal genetic blueprint.

There’s this famous sentence at the end of the paper where Watson and Crick describe the structure of DNA.

They say it has, quote, “not escaped our notice” that the structure they describe implies a way for DNA to copy itself.

Meaning they knew exactly how significant it was going to be.

And the paper describing k-abe has something similar at the end.

The authors say, quote: “Although k-abe was developed under emergency conditions for a devastating neonatal-onset metabolic disorder, we anticipate that rapid deployment of patient-specific gene-editing therapies will become routine for many genetic diseases.”

It definitely hasn’t escaped my notice that there could be many, many more lucky KJs in the future.

And I can’t wait to see it.

[♪OUTRO]