The company that just got approval to sell the first gene-editing treatment in history, for sickle-cell disease, is already looking for an ordinary drug that could take its place.

Vertex Pharmaceuticals has a 50-person team working “to make a pill that doesn’t do gene editing at all,” says David Altshuler, head of research at the Boston drug company.

“We’re trying to out-innovate ourselves,” he says. 

Vertex won approval in the US to sell the world’s first treatment using CRISPR, the gene-editing technique, on December 8. It took eight years to develop, and at huge expense. Regulatory documents filed with the government during the approval process exceeded a million pages.

Yet now that medicine’s CRISPR era has begun, some of the technique’s limitations are already visible.

The treatment, called Casgevy, is both tough on patients and hugely expensive. Patients must spend several weeks in a hospital as doctors remove, genetically edit, and then reintroduce their bone-marrow stem cells, which make blood. The treatment will cost $2.2 million, not including hospital costs, according to Vertex.

The company proved the gene fix can be a permanent remedy for people who have the most severe sickle-cell symptoms. These individuals, numbering around 16,000 in the U.S., suffer recurring pain crises when misshapen red blood cells block blood vessels in their bodies.

But it’s unclear how many Americans will opt for gene editing. In an opinion column for MIT Technology Review, one patient who got the treatment, Jimi Olaghere, said the bone-marrow replacement an “intense months-long journey” that will create barriers to access.

Previously, several gene therapies have floundered in the marketplace because of a combination of high prices and too few patients.

“It’s simultaneously a miracle and has a drawback that prevents wide use,” says Geoffrey von Maltzahn, a partner at Flagship Pioneering, who leads biotech ventures but was not involved in the sickle-cell treatment. “That is a common duality.”

Such drawbacks are why a pill to alleviate sickle-cell, if developed, could sweep CRISPR from the playing field. A pill version could also resolve a brewing moral dilemma: Vertex so far has no plans to offer its gene-editing treatment in those countries where sickle-cell is most common.

A wide ribbon of lower-income nations across the middle of Africa, including Nigeria and Ghana, account for 80% of sickle-cell cases but, according to US researchers, lack the hospitals, medical expertise, and money to implement this complex intervention.

“One question I get a lot is: How are we going to get to the rest of the world?” says Altshuler. “And I think the answer is not by trying to do bone-marrow transplants in the rest of the world. It’s just too resource intensive, and the infrastructure is not there. I think the goal will be achieved sooner by finding another modality, like a pill that can be distributed much more effectively.”

Three strategies

In an interview with MIT Technology Review, Altshuler outlined three ideas Vertex is exploring to improve on its breakthrough CRISPR treatment.

One is to come up with a substitute for the intense chemotherapy that’s used to kill a person’s bone marrow and make space for the edited cells to take over. Vertex and other gene-editing companies, like Beam Therapeutics, say they are looking into gentler methods that could make the procedure easier for patients.

A second strategy Vertex and other companies are exploring is called “in vivo” editing. That’s when gene-editing molecules are dripped directly into a person’s veins, or even injected like a vaccine, no transplant needed.

To achieve in vivo editing for blood diseases, research groups are trying to develop homing systems—viruses or special nanoparticles—that would convey CRISPR directly to a person’s blood-making stem cells. Such “single shot” editing concepts have won substantial support from the Bill & Melinda Gates Foundation, which thinks it could help solve sickle-cell and HIV in Africa. But it remains at an experimental stage, and some question if it will ever be possible.

The final idea is a conventional drug, the kind you swallow. That would be the easiest to distribute where it’s needed. Angela Koehler, a biochemist at MIT, says “broadly accessible” drugs with a “low barrier to access” would have the greatest impact on sickle-cell disease globally.

“This does not diminish my excitement about the CRISPR-based approaches, but it partially explains the motivations of folks trying to develop ‘traditional’ drugs,” says Koehler.

Keep innovating

Sickle-cell is caused by defects in hemoglobin, the oxygen-carrying molecule in red blood cells. The CRISPR treatment stops the worst disease symptoms by making a targeted DNA edit that turns on “fetal hemoglobin,” a second version that we all have but is largely inactive after we’re born.

By early 2019, Altshuler says, he had seen results from the first gene-edited patients who volunteered for the company’s trial. It was clear then that the theory was true: turning up fetal hemoglobin was a cure.

Within weeks of seeing those results, Altshuler says he’d launched a hunt for a conventional drug that could do the same thing, even as the CRISPR program steamed ahead. “The goal is to achieve a similar profile with a pill instead of a gene editing,” he says.

Reaching the whole world with a treatment was part of the motivation, but it wasn’t the only one. Part of what is driving Vertex is a painful lesson it learned following the 2011 launch of its breakthrough drug for hepatitis C, called Incivek. The drug had the fastest increase in sales for any product in history at the time, reaching $1.5 billion in a year.

Yet within three years, Vertex had to stop selling Incivek after a competitor, Gilead Sciences, came up with a more effective alternative with fewer side effects. 

The brutal lesson: keep innovating.

“Something I have never understood about biopharma: they discover the first medicine in a disease, and let other people eat their lunch,” Altshuler says. “They stop doing research and wait.” 

Pill hunt

The pill hunt remains shrouded in secrecy—Altshuler won’t reveal any of the details, saying the lack of information in the public domain is part of what makes it an attractive project. 

But it’s likely that Vertex’s search centers on the same biological “target” that CRISPR changes. That is a gene called BCL11A, which acts like a switch controlling fetal hemoglobin. Gene editing turns that gene down, allowing fetal hemoglobin to rise.

It’s not easy to get an ordinary drug to copy that effect. The tricky part is that the BCL11A gene manufactures a transcription factor, a type of protein that’s floppy and formless and lacks the precise kinks and corners that chemists can aim drugs at. Indeed, such molecules have the reputation of being “undruggable.”

According to Altshuler, no marketed drug currently works by binding to a transcription factor.

Although the hunt for a drug has so far been low key and out of sight, clues have started to spill out, including some from other companies pursuing similar goals. This week, at a major blood-disorders meeting, the pharmaceutical company Novartis said it had screened several thousand molecules and found some that were able to raise fetal hemoglobin.

Separately, a team at Children’s Hospital in Boston said at the same meeting it had made discoveries about how the BCL11A protein folds, highlighting potential ways drugs could act on it.

That lab is led by Stuart Orkin, a scientist whose discoveries about the fetal-hemoglobin switch we recently profiled in MIT Technology Review. “Some people are trying to find new targets, but I don’t think there is anything else worth studying,” says Orkin. “I think it’s the only one that will get us to the other side of the problem.”

Orkin says he’s been looking for a drug, too, but those attempts, some in collaboration with Koehler, have not yet paid off. “I can say we’ve tried a lot of things that don’t work,” he says.

Orkin also still believes gene editing will be a better treatment, if you can get it. “If I had a child and the choice was a cure versus taking pills for life, I would go for the editing. If you can fix it, I would,” he says. “But many patients are not ready for the rigors of transplant, and many are not in a setting where it can be done. There aren’t enough hospitals or physicians.”

And that is the irony of CRISPR’s first treatment. It can cure individuals but can’t yet conquer a disease. In fact, the problem of sickle-cell is only expanding. That is because countries with high rates of this inherited condition also have booming populations. Every year, more people, not fewer, suffer with the disease. CRISPR can’t yet reverse the trend, but a pill might.

“It’s solved from a disease standpoint, but not a burden-of-disease standpoint,” says Orkin. “That is the next chapter. Sickle-cell is a big problem. And it’s growing, not shrinking.”

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.

Covid shots do an admirable job of boosting our immune response enough to protect against serious illness, but they don’t boost immunity in the one spot we’d like them to: our airways. That’s why researchers have been working on vaccines you breathe into your lungs or spray into your nose. The idea is that these vaccines will elicit an immune response in the mucous membranes of your respiratory tract that might help stave off infection or, if you do become infected, make you less likely to transmit the virus.

These “mucosal” covid vaccines aren’t available in the US or Europe, but they are in other parts of the world. When we last reported on efforts to develop a mucosal vaccine in 2022, two had been approved in China and India. Now five are in use in China, India, Iran, Indonesia, Morocco, and Russia. A couple dozen more candidates are in clinical trials. And many, many more are on the way.

This week I came across a paper from a team in China developing another inhalable vaccine. This vaccine differs from most others in at least one notable way: it is a powder, which means that it’s shelf stable and doesn’t need refrigeration. That would make it easier to transport and deliver, especially to places where refrigeration is difficult.

This candidate won’t be available anytime soon. It’s still in preclinical development, along with more than a hundred other similar vaccines. But now that we’re almost four years out from the start of the pandemic, it seems like a good time to take stock. When will the US get its first mucosal covid vaccine? What will it look like? And will it work as intended?

What is the timeline?

Only one mucosal vaccine—FluMist—has ever been approved in the US, and that happened two decades ago. But efforts to develop one for covid are moving quickly. So when might the US see its first mucosal covid vaccine? “Maybe never. But I think there’s increasing likelihood that it may happen before the end of 2024,” speculated Eric Topol, a cardiologist who has been following Covid research closely since 2020, in a recent newsletter.

The federal government is working to speed things along with an injection of cash through Project NextGen, a $5 billion effort to usher new and improved covid vaccines to market. In October, the Department of Health and Human Services announced that nearly $20 million would go to two companies developing mucosal vaccines—Codagenix and CastleVax. That money will help the companies gear up for studies to test how well their vaccines work to prevent symptomatic infections. 

Codagenix’s candidate, a nasal vaccine called CoviLiv, is already part of a phase 3 global efficacy trial coordinated by the World Health Organization. And in October, the company reported results from a safety study in adults in the UK who had never been vaccinated for covid before. The nasal mist prompted robust immunity, at least as measured by markers in the blood. But evidence of an immune response in the blood doesn’t necessarily indicate an immune response in the mucosal lining of the airways. Or, as one physician puts it, “just like the ‘far, dark side of the Moon’, which is invisible from the earth, the mucosal response to pathogens is a far, dark side of immunity that is poorly or not visible from the peripheral blood and more complicated to probe than systemic immunity.” 

What’s the best way to elicit mucosal immunity?

TBD. Different groups are trying a variety of strategies. The goal is to induce immunity in the airways that is robust, broad, and durable. But which strategy will succeed is a bit of a question mark at the moment. Mucosal vaccines fall into a few categories depending on how they’re administered and the platform they use. Some are sprays that are squirted into the nose (CovLiv, for example). Others are meant to be inhaled into the lungs (such as one developed by CanSinBIO in China). 

Sometimes these two routes of administration get lumped together, but they actually are very different, says Mangalakumari Jeyanathan, a researcher at McMaster University and coauthor of an editorial that accompanies the new inhalable-vaccine paper. With a nasal vaccine, the contents go into the nasal cavity. But Jeyanathan thinks inhaled vaccines, which go deep into the lungs, are likely to work better. Her team’s research suggests that nasal vaccines induce immune responses only in the upper respiratory tract, not in the lower respiratory tract. That means, she says, that if the vaccine doesn’t prevent infection, the lungs are still vulnerable, and “we really need the immune responses to prevent any sort of serious damage to the lung.”

The vaccine outlined in the recent Nature paper is meant to be inhaled. It is a subunit vaccine, meaning it contains a portion of the pathogen. In this case, the subunit is actually a piece of cholera toxin that has been engineered to display a portion of SARS-CoV-2. These proteins are placed into microcapsules small enough to travel deep into the lungs.

I’ve been vaccinated, and I had covid. Don’t I already have good mucosal immunity?

Maybe. Studies show that people who have been infected and vaccinated do have better mucosal immunity than people who have been vaccinated but not infected. But Jeyanathan says her group has also seen quite a few people who have been infected and don’t have much mucosal immunity in their lungs. When they wash the lungs with saline to collect samples from the lower respiratory tract, they don’t find detectable T-cell responses. “It’s really sort of very strange,” she says. 

But it’s not just about whether you’ve got mucosal immunity. It also matters how broad that immunity is. One of the most problematic things about SARS-CoV-2 is that it’s constantly evolving. Each month seems to bring a new variant. The changes mainly affect the spike protein, the target of all current vaccines. But some groups are working to variant-proof their mucosal vaccines. Jeyanathan’s group is putting in parts of the interior of the covid virus, which aren’t apt to change as quickly as the portion that binds to cells. “So that way, we don’t need to do this variant-chasing approach,” she says. 

What will it take to show that a mucosal vaccine works?

Regulators are still trying to work out how to measure success. In some cases, companies can demonstrate vaccine effectiveness through surrogate markers such as antibody levels. That’s how the latest boosters were approved. But with mucosal vaccines, it’s not clear what surrogate marker would be most useful. Antibody levels in the nose or mouth? Or the abundance of certain immune cells? 

In an editorial published a year ago, Peter Marks from the FDA and colleagues argued that vaccines that differ substantially from those already approved might need to be tested in large, randomized clinical trials. What we really want to see is that these next-generation vaccines outperform existing vaccines and curb transmission. That data isn’t in yet, and it could take years before we know whether mucosal vaccines actually do what we hope they will: stop the virus from spreading. 

Another thing

Vertex, maker of the recently approved CRISPR sickle-cell therapy, has agreed to pay tens of millions of dollars to avoid any patent infringement lawsuits. Antonio Regalado has the story.

Read more from MIT Technology Review’s archive

When the first two mucosal vaccines were approved in 2022, we published an explainer by Jessica Hamelzou. 

Wouldn’t it be wonderful if we had a vaccine that worked against all coronaviruses? One team’s mosaic nanoparticle may be the key to success, reports Adam Piore.  

From around the web 

The first gene therapies for sickle-cell disease have arrived, but patients in the countries with the greatest burden of the disease won’t be able to access them.  (NYT)

CAR-T, a cell therapy developed to treat cancer, has seemingly eliminated autoimmune disease in 15 patients (Nature)

The US Supreme Court plans to review a case that could affect access to the abortion medication mifepristone. (Washington Post)

A single hormone seems to be to blame for morning sickness, a discovery that may lead to better treatments. (NYT)

Vertex has been in the headlines for its newly approved sickle-cell therapy, but the company is also closing in on a non-opioid painkiller. Here’s a fascinating deep dive into the backstory. (Stat)