A research paper published a decade ago touched off a biomedical revolution that has made careers, spawned companies and drawn billions of dollars of investment. By the end of the year, the gene editing technology that paper described could win Food and Drug Administration approval as part of a powerful new treatment for sickle cell disease.

Now Nobel Prize-winning science, CRISPR gene editing is at the heart of the biotechnology industry’s latest Big Bang. It’s adaptable and efficient, putting the precise alteration of DNA within easy reach of academic scientists and drug startups alike.

Since 2012, when research by Jennifer Doudna and Emmanuelle Charpentier was published in Science, more than a dozen biotech companies have sprung forward to capitalize on the possibilities they and other scientists unlocked.

This new generation has joined early adopters CRISPR Therapeutics, Editas Medicine and Intellia Therapeutics, offering various twists and tweaks to improve on the original CRISPR technology. They’re also taking aim at a wider array of illnesses, from ALS to heart disease.

Many are led by or employ scientists and post-doctoral students trained in the laboratories of the University of California, Berkeley and the Broad Institute of MIT and Harvard, the academic institutions most closely linked to CRISPR gene editing research.

The research diaspora mirrors a broader trend in the life sciences. According to Feng Zhang, a member of the Broad and a pioneering CRISPR expert, the lines between academia and industry are “blending” more than before.

“The door is open in both directions,” Zhang said. “We need the flow of talent to be as porous as possible” to speed CRISPR research.

And, as happened with new drugmaking technologies before CRISPR, large pharmaceutical companies have moved in, placing bets on the technology’s potential.

“Large pharma is recognizing that this has the potential to be the future of medicine,” said Benjamin Oakes, co-founder and CEO of Scribe Therapeutics, an early-stage CRISPR drug developer now working with Eli Lilly and Sanofi.

The first glimpse of that future could come in early December, when the FDA is set to decide on approval of that sickle cell treatment, known as exa-cel and developed by CRISPR Therapeutics and Vertex Pharmaceuticals.

A biotech foundation

Often likened to a pair of genetic scissors, CRISPR editing at its simplest involves just a few specialized components. A strip of engineered RNA acts as a guide, shepherding the editing machinery to a corresponding stretch of DNA in a cell. If the sequences match, an enzyme called Cas9 will cut through the DNA double helix at that precise spot.

When this happens, the cell moves to repair the double-stranded DNA break. The process can inactivate the gene in question — useful for treating diseases caused by harmful protein production. Researchers can also take advantage of the cut made by Cas9 to correct the target gene or insert a new one by pairing the editing complex with a DNA template.

Exa-cel, Vertex and CRISPR Therapeutics’ drug, relies on the former approach. A patient’s own stem cells are collected and isolated in a laboratory, where CRISPR/Cas9 is used to cut a particular section of a gene called BCL11A.

This disruption causes the cells, once reinfused back into the patient, to produce high levels of fetal hemoglobin, an oxygen-carrying protein which the body stops making soon after infancy. High levels of fetal hemoglobin are thought to counteract the red blood cell sickling that’s characteristic of the disease and the cause of its symptoms.

Before CRISPR, gene editing was limited to older technologies like zinc finger nucleases, and transcription activator-like effector proteins, or TALENs.

Zinc finger nucleases are enzymes that also can cut specific gene sequences, while TALEN-based editing uses the eponymous protein to do the job. But both are expensive and time-consuming to produce and lack CRISPR’s specificity.

“The CRISPR revolution came around at the right time,” said Mitch Finer, CEO of Life Edit Therapeutics and former chief scientific officer of Bluebird bio, which has developed a rival sickle cell treatment to exa-cel. “It’s one protein, and all you have to do is change up the guide RNA. That’s what was so attractive.”

Doudna and Charpentier’s paper, as well as research by Zhang and others, led to the quick formation of a trio of companies focused on turning CRISPR science into new medicines.

Charpentier launched CRISPR Therapeutics in 2013 with Shaun Foy, a venture capitalist, and Rodger Novak, who had been an executive at Sanofi. Around the same time, Doudna joined other leading scientists in the field, including Zhang, George Church, David Liu and Keith Joung, to introduce Editas Medicine.

But Doudna quit Editas in 2014 as the co-founders tussled over who owned the intellectual property for CRISPR/Cas9. She later co-founded Intellia Therapeutics, working with Atlas Venture and Caribou Biosciences, a company she had launched several years prior.

According to Novak, academic innovation provided the necessary spark to start biotech’s CRISPR revolution, particularly as it came alongside the emergence of other technologies like messenger RNA and cheaper gene sequencing.

“Technology wise, around that time, there was some light on the horizon and things came together relatively nicely,” he told BioPharma Dive in a recent interview.

CRISPR Therapeutics, Intellia and Editas drove the translation of CRISPR into the clinic, achieving some of the field’s firsts. Exa-cel, for instance, became the first medicine made with the technology to be tested in humans in a biotech trial. And in 2021, Intellia proved CRISPR could work “in vivo,” or directly inside the body rather than via extracted cells.

But they also hit difficulties, too. Progress was greatest in rare diseases of the eye and blood, areas of the body that are relatively easier to reach — shaping which conditions the companies aimed for first. CRISPR/Cas9, with its proclivity to cut through both strands of DNA, also isn’t the best tool to address every kind of genetic mutation, spurring research into other approaches.

New directions

As gene editing research advanced, scientists unearthed different techniques for editing DNA as well as other CRISPR-associated enzymes to do the job.

Their discoveries led to a stream of academic literature on how CRISPR could be improved and made more precise. Zhang and researchers working with him at the Broad studied Cas12 and Cas13. Joung, at his lab at Massachusetts General Hospital, engineered CRISPR/Cas9 systems to better avoid off-target effects. Liu and his team published in 2016 and 2019, respectively, landmark papers on base and prime editing, which offered ways to edit single nucleotides without cutting both DNA strands.

“We now have at our disposal more capabilities, so that we can pick the best one for the disease we're trying to treat,” Zhang said.

He likened the advancements to a bigger toolbox, containing just the right equipment for specific jobs. “If your house didn't have water, there’s a problem with the pipe, and instead of fixing the pipe you get water from somewhere else — that’s the approach that's taken with current sickle cell disease treatments,” Zhang said, referring to exa-cel and Bluebird’s treatment, which uses an engineered virus to add a new gene to patient stem cells.

“With more tools in the toolbox, we'll have a better chance of being able to fix the pipe,” Zhang added.

The discoveries led to new companies, like Beam Therapeutics, which was founded by Liu, Zhang and Joung to develop base editing into medicines. A group of venture investors and life sciences researchers including Joung started Verve Therapeutics in 2018. And Liu later co-founded Prime Medicine around prime editing.

These companies, and others, were launched even as legal battles continued between the Broad and Berkeley over rights to the original CRISPR invention. (Federal patent officials issued a ruling in 2022 determining the legal rights to the foundational technology belong to the Broad.)

The Broad has said it believes in “open access” to CRISPR research. Since 2014, the institution has granted licenses to companies and scientists looking to build on the existing technology.

An expanding group of venture firms, including Arch Venture Partners, F-Prime Capital, GV, Atlas Venture and Newpath Partners, has emerged as common backers of this second generation of CRISPR companies.

The value of private financings also swelled. Early on, CRISPR-focused biotechs raised between $15 million and $43 million in their initial Series A rounds. Their successors often raised much more: Prime Medicine emerged from stealth in 2021 with $315 million in hand from its Series A and B rounds, for instance.

The influx of money helped fund grand ambitions and broad development goals. “I certainly would love to become the next Vertex or Biogen,” Keith Gottesdiener, then the CEO of Prime Medicine, said in a 2021 interview with BioPharma Dive.

Some of these later companies also benefited from going public during a peak in biotech valuations. Beam went out in 2020, followed by Verve in 2021, when it hit Wall Street with one of the year’s largest IPOs. Even in 2022, when the sector was experiencing the beginnings of a funding drought, Prime Medicine was able to pull off an IPO.

Still, these companies haven’t gotten far in the pursuit of treating people. Beam began testing a “first-of-its-kind” gene editing medicine for cancer in September, the first time a base editing medicine has entered human trials.

An expanding ecosystem

CRISPR is now no longer the domain of just a handful of biotechs. A larger ecosystem exists, as more gene editing startups have continued to crop up.

These companies are working with other CRISPR enzymes, such as Cas12, Cas13, Cas14 and CasΦ, and aim to sidestep problems like delivery and off-target editing. (Older gene editing companies, like Editas, Caribou and Beam, are also experimenting with new enzymes, too.)

This fresh slate of Cas molecules has emerged along with a new generation of scientists. Researchers who completed their PhDs and post-doctoral fellowships under gene editing pioneers like Doudna, Zhang and Liu are launching companies of their own.

“Abandoning false modesty, we're UC Berkeley,” said Fyodor Urnov, a professor of molecular and cell biology at UC Berkeley and an expert in genetic medicine. “We're the best public research university in the world. It's an elite training school.”

For example, Janice Chen and Lucas Harrington, two Berkeley researchers who worked with Doudna on a 2018 paper detailing Cas12, founded Mammoth Biosciences with her and a Stanford University colleague, Trevor Martin. Based in the San Francisco Bay Area, Mammoth is now working with both Cas14 and CasΦ proteins, which are smaller than the original enzyme.

“We’re still developing tools to understand what are high standard edits, or what are other off-target edits,” said Chen, now Mammoth’s chief technology officer. “The technology is advancing, but then also the tools to understand the safety profile.”

In its early days, Mammoth focused on both diagnostics and medicines, believing CRISPR could improve upon existing methods in identifying cancer targets or viral infections. The biotech partnered with Vertex in 2021, and Bayer a year later. It has since trimmed back its diagnostics work.

Like Zhang, Mammoth’s founders see the latest iterations of CRISPR as a toolkit.

“We want to have the right technology available for the disease so we can be driven by the science and the disease biology,” Martin said. Then, “it’s not that we have a hammer, so everything has to look like a nail. We can choose the right technology for the disease, rather than having to fit everything into a certain box.”

Doudna is also associated with other biotechs such as Scribe Therapeutics, which she co-founded with Oakes, one of her former students. Oakes, who once studied zinc finger nucleases, came to Berkeley in 2013 after the publication of that first CRISPR/Cas9 paper by Doudna and Charpentier.

“That problem that we were brute force working to solve was solved in a much more elegant way,” said the Scribe CEO, who co-authored a paper on CRISPR/CasX in 2019.

The backing of young researchers by scientists at Berkeley and the Broad has helped along the evolution of new CRISPR-based technologies. So, too, has the technology’s spread throughout the scientific community, despite the legal battling over CRISPR patents between Berkeley and the Broad.

“Licensing the technology, on a non-exclusive basis for different areas, has been really, really good,” said Zhang, of the Broad. “It’s accelerated research and application development.”

Setbacks and public sentiment

The rapid growth of the gene editing sector has come with its share of research stops and starts.

As the initial companies raced to begin clinical trials, federal regulators in the U.S. proceeded more warily. In 2018, the FDA paused Vertex and CRISPR Therapeutics’ plans to start their first study of exa-cel. Editas also ran into delays when the FDA imposed a partial clinical hold for its sickle cell disease therapy in 2021.

Both Beam and Verve had similar problems as they tried to advance their base editing programs into clinical testing, receiving clinical hold orders from the FDA last summer and fall.

The temporary pauses reflected regulatory caution on the safety of CRISPR gene editing and its use in humans. In particular, the FDA appears to be closely watching tests of in vivo CRISPR medicines for any signs CRISPR changes could be inadvertently made to sperm or egg cells  — so-called germline edits.

“Our view is that this is the FDA taking a very considered view of the space,” said Intellia CEO John Leonard in response to questions on an August call about a recent request made by the agency.

Intellia conducted testing of its first in vivo candidate outside of the U.S., and recently scrapped plans to include U.S. patients in testing of its second following the FDA’s ask. The company intends to open up U.S. trial sites as part of late-stage studies it’s now preparing.

Other safety concerns have cropped up too, such as with Graphite Bio’s sickle cell treatment nula-cel, which the company stopped testing after reporting a serious side effect.

In most cases, though, the FDA has lifted the holds it’s imposed, allowing testing to advance and paving the way for the agency’s current review of exa-cel.

That looming approval decision will again put CRISPR gene editing squarely in the public eye. While biotechs are using the technology to treat diseases solely via edits to somatic cells, the field is still shadowed by the actions of Chinese scientist He Jiankui. In 2018, He stunned the scientific world by announcing he had edited a pair of embryos that were implanted and brought to term, sparking condemnation and renewed calls to restrict germline editing.

Even before the controversy, the Broad had put in place safeguards against experiments like He’s. Now, the institution maintains “any human clinical use must be consistent with all laws and regulations,” and does not license their technology for editing human egg and sperm cells.

Looking ahead

Even as a down biotech market has stressed young drugmakers, gene editing companies continue to draw investment.

Prime’s IPO, for example, raised $175 million last October — a rare IPO success in a down year. New gene editing companies continue to emerge, too, such as Tome Biosciences and Tune Therapeutics.

Others, meanwhile, are applying CRISPR principles in different ways. Boston-based Chroma Medicine, which raised $135 million in venture funding this March, is crafting drugs to alter the epigenome.

From an R&D perspective, researchers in the field hope to make advances in several areas. First, prove that CRISPR-based gene editing can work in a wider variety of diseases. Many of the initial programs are for eye-related conditions, sickle cell disease or beta thalassemia, but there are many other possible targets, said Urnov, who co-founded Tune and consults with Vertex.

Second, delivery remains a challenge. Current genetic medicines can readily reach those parts of the body that are easily accessible, such as the eye, blood or liver. As a result, diseases affecting other tissues, like the muscle and brain, remain challenging to treat, even if the genetic errors causing them are well understood.

And there are still concerns about the possibility of off-target edits with CRISPR-based therapies. The FDA’s ongoing review of Vertex and CRISPR Therapeutics’ medicine could give a window into the agency’s comfort with this risk.

From an industry perspective, commercialization of genetic medicines remains a question mark. While they promise dramatic benefits, their high price tags and complex manufacturing could present marketing hurdles. Outside of Novartis’ spinal muscular atrophy drug Zolgensma, sales of the gene replacement therapies approved to date have not taken off.

“The for-profit sector really understands how to commercialize medicines where you put the patient on a lifetime of treatment,” said Urnov. With gene therapy, most patients will likely receive treatment once.

“At the end of day, patients aren't going to care about the modality,” Chen said. “They just want to know: is it safe and does it work? That's the ultimate end goal.”

Ned Pagliarulo contributed reporting.

By early December, the Food and Drug Administration will decide on approval of a genetic medicine for sickle cell disease, potentially offering people with the rare blood condition a new, sought-after treatment option.

The medicine’s developers, Vertex Pharmaceuticals and CRISPR Therapeutics, are already preparing for what happens next should they win approval. Their treatment, called exa-cel, is difficult to make, requiring a patient’s own blood stem cells to be extracted and then engineered using CRISPR gene editing technology. It’s also likely to come at an extremely high price, possibly creating a sticking point with insurers.

For Vertex, which became one of the world’s largest biotechnology companies by developing oral drugs for cystic fibrosis, exa-cel presents new challenges. Launching a therapy like this calls for an “exquisite amount of choreography” between all parties involved, including the patients, the treatment centers and Vertex itself, according to the company’s chief operating officer Stuart Arbuckle.

“To do that requires a lot of investment in systems and processes that’ll manage that whole process and ensure everybody is kept in the loop,” Arbuckle said Oct. 25, during an event hosted by BioPharma Dive. “There's a lot of work being done on the front end, so that hopefully when the approval comes through, we're ready to go and get this medicine to patients.”

Estimates hold that sickle cell affects more than 100,000 people in the U.S. and millions more in the rest of the world, with the disease most commonly found in those with African ancestry. It’s caused by mutations that make red blood cells crescent-shaped and less flexible, which can in turn block the flow of blood through the body.

A lifelong illness, sickle cell can cause strokes, organ damage and episodes of intense pain known as vaso-occlusive crises. Only a few treatments for the disease are available, and the only known cure is a bone marrow transplant. Research indicates that people with this disease have a life expectancy two decades shorter than the general population.

Vertex and CRISPR Therapeutics hope to provide a potentially one-time therapy in exa-cel, which Vertex licensed in 2017 after previously partnering with the smaller biotech. Vertex says its drug development strategy revolves around picking targets where the biology of the disease is well understood and there is significant need for new treatments. Sickle cell fits that strategy well, according to David Altshuler, the company’s chief scientific officer.

Clinical testing has found exa-cel alleviates the most serious and impactful effects of sickle cell, as well as another rare blood disorder, beta-thalassemia. Results released this year showed that among 17 evaluable sickle cell patients, 16 were free of pain crises for at least one year after receiving Vertex and CRISPR Therapeutics’ therapy. (Another 18 have been treated, but hadn’t been followed for longer than 12 months when the data were analyzed.)

“Everything we've seen to date in the clinical trials supports the idea that, from a gene editing point of view, this is certainly an extremely strong, if not optimal, approach,” Altshuler said.

Still, exa-cel probably won’t be attractive to all sickle cell patients. To make and administer the therapy is laborious, first requiring a referral from a hematologist. If the patient is eligible, their cells are collected and shipped to a manufacturing facility where they’re genetically edited to express a form of an essential protein called hemoglobin.

The cells are then shipped back to a treatment facility that infuses them into the patient’s bone marrow. But to make sure there’s enough room for these new cells, patients first undergo myeloablation — a chemotherapy regimen that can be very difficult on their bodies and comes with the risk of infertility. Older patients may not be healthy enough to receive this treatment.

“This is an extensive and expensive process,” Arbuckle said.

Vertex says it’s trying to get ahead of these expected obstacles in a few ways. One, according to Arbuckle, is identifying and qualifying the treatment centers capable of doing this complex procedure.

Another is connecting with payers ahead of the approval decision, to ensure they understand the burdens associated with sickle cell, the technology underpinning exa-cel, as well as “what's coming, so that they can begin to think about how they're going to pay and budget for that kind of technology.”

“Most healthcare systems are essentially set up to think about and pay for chronic medicines,” Arbuckle said. “Clearly these types of one-time, potential treatments really challenge that paradigm.”

Arbuckle added that, as the industry tries to determine the most appropriate payment models for gene therapies, Vertex is learning from others, while also drawing on its own experience selling cystic fibrosis drugs.

“No two payers are created equal in some ways,” he said. “And so being flexible about the type of payment models that we’re looking at, I think is going to be the way forward, as opposed to trying to approach this with a one-size-fits-all approach.” Arbuckle noted how installment payment, or annuity, models have not gained traction with insurers, despite initial expectations they would be attractive.

One boost could from the federal government, which in 2026 plans to launch a pilot to test how state Medicaid agencies can pay for sickle cell therapies like exa-cel. “I think it’s a great signal from the administration,” Arbuckle said.

So far, approved gene therapies have had mixed commercial success. That may be contributing to the view of exa-cel on Wall Street. The investment firm Cantor Fitzgerald, for instance, recently downgraded its rating of CRISPR Therapeutics, as analysts were “tepid” on the therapy’s potential upcoming launch.

“Driven by Vertex's support and experience, we expect exa-cel to become the leading therapy for [sickle cell disease],” analyst Eric Schmidt wrote in an Oct. 17 note to clients. “However, it could take time to break down the many potential barriers to adoption.”

Schmidt and his team have reduced their forecast for exa-cel and anticipate sales falling short of consensus estimates of $150 million in 2024.

Sponsored content

By Bio-Rad

Innovative cell and gene therapies could hold the keys to treating and potentially curing a wide range of genetic and acquired diseases. Among the arsenal of tools available to researchers and biopharmaceutical experts, lentiviral vectors have long been recognized as a versatile platform for delivering genetic material into target cells. However, as the field progresses and therapies move closer to clinical applications, addressing and overcoming common pitfalls associated with lentiviral cell and gene therapies becomes crucial.

Confidence in the therapeutic potential of lentiviruses hinges on accurately quantifying and monitoring the viral load during production and throughout the therapy process. To meet this demand for precision and sensitivity, many experts turn to Droplet Digital™ PCR (ddPCR™) technology. By harnessing the power and absolute quantification of ddPCR technology, cell and gene therapy manufacturers can confidently navigate the intricacies of lentiviral cell and gene therapies, bringing us closer to a future where these groundbreaking treatments become a reality for countless individuals in need.

Understanding Your Technology Options

When it comes to quantifying nucleic acids in lentiviral cell and gene therapies, choosing the right technology is essential. Among the options available, the ddPCR workflow is high-quality and reliable data. Unlike traditional PCR methods that rely on amplification and fluorescence signal detection, ddPCR technology partitions the sample into 20,000 individual reactions within water-in-oil droplets. This partitioning enables absolute quantification of the target, providing accurate measurements of target concentrations without the need for standard curves.

Compared to other digital PCR technologies, ddPCR technology offers several advantages that make it particularly well-suited for lentiviral cell and gene therapies. Firstly, the high number of partitions generated by ddPCR technology ensures robust and statistically significant data, minimizing the impact of low-abundance targets or sample heterogeneity. Secondly, the droplet-based format of ddPCR assays allows for higher tolerance to inhibitors commonly found in biological samples, ensuring accurate quantification even in complex matrices. These features make ddPCR technology a reliable and precise tool for cell and gene therapy manufacturers seeking the sensitivity and precision required to navigate the challenges associated with lentiviral cell and gene therapies.

Do You Really Know Your Lentiviral Titer?

The precise determination of infectious viral titer is a critical factor in lentiviral cell and gene therapies, directly influencing treatment outcomes and patient safety. Inaccurate viral titer determination can lead to detrimental effects, including under-dosing or over-dosing of patients, potentially compromising the efficacy of treatments or causing adverse reactions.

Biotechnology experts are already leveraging ddPCR technology to measure lentiviral vectors infectious titers.. For example, scientists from Biogen published a study in Human Gene Therapy Methods describing their ddPCR method and reporting its superior performance compared to qPCR and fluorescence-activated cell sorting (FACS). Similarly, Lonza scientists have presented their development of high-throughput ddPCR assays for lentivirus infectious titer determination, saying they chose ddPCR technology because it “has emerged as a reliable, cutting-edge technology to quantify the absolute copy number of any gene of interest without using a standard curve.”

Getting Your Lentiviral Vector Copy Number Right

In addition to viral titer, cell and gene therapy developers need to know how efficiently their lentiviral vector integrates the gene of interest into the target cells. Failed transgene integration can offer no therapeutic effect, while vector copy numbers that are too high can result in overly potent and potentially dangerous products. In 2020, NIH researchers demonstrated the utility of ddPCR assays for assessing the average number of lentiviral vectors integrated into multiple types of engineered T cell therapies. In 2022, another group of researchers enabled greater industry standardization by developing lentiviral standards for determining vector copy number assay sensitivity, subsequently using these standards “to show the superior precision of Droplet Digital PCR over quantitative PCR for vector copy number determination.”

Realizing the Promise of Lentiviral Cell and Gene Therapies

In summary, the adoption of ddPCR technology has revolutionized the landscape of cell and gene therapy development and manufacturing. Its versatility as a powerful tool for accurate quantitation of lentiviral titer, vector copy number, and much more has profound implications for improving the safety and efficacy of these advanced therapies. From the early stages of development to the scale-up of commercial manufacturing, ddPCR assays provide scientists and manufacturers with the sensitivity and precision needed to navigate the challenges of cell and gene therapy production confidently. As the field continues to evolve, ddPCR technology remains at the forefront, driving advancements and enabling breakthroughs in the realm of personalized medicine.

Visit our website to explore advanced solutions for cell and gene therapies

Developing a new drug is a long, expensive process that comes with a high risk of failure, often because would-be medicines are unsafe or ineffective.

For companies specializing in cell or gene therapies, an equally pressing concern is figuring out how to reliably make their products. Unlike small molecule or antibody drugs, genetic medicines typically involve a variety of specialized parts woven together through a complex process.

"Ex vivo," or outside-the-body, treatments can involve a multi-week process for collecting, multiplying and modifying a patient's cells in a laboratory. Even the simpler "in vivo" therapies have multiple pieces, including engineered viruses and synthetic genetic material, that are challenging to produce at scale.

The approvals of a dozen cell- and gene-based medicines for cancer and inherited diseases in recent years has given young drugmakers a path to pursue. But most of those approvals were won by large pharmaceutical or biotechnology companies that invested heavily in manufacturing. Startups, by contrast, don't yet have that luxury.

Still, cell and gene therapy research is booming. More than 2,200 clinical trials testing these types of treatments were ongoing globally as of last year, according to the Alliance for Regenerative Medicine. The surge has often outstripped the capacity of large contract manufacturers, leaving startups facing waitlists that can stretch one to two years.

A growing group of new manufacturers aim to help. Since 2017, at least half a dozen companies have launched with plans to ease the "bottlenecks" slowing down aspiring cell and gene therapy developers. Many have been started by veterans of the young field and gotten the backing of top venture firms. Here's what they aim to accomplish and how their work is progressing:

What are the main bottlenecks in cell and gene therapy manufacturing?

Cell and gene therapies involve materials that aren't used in many of the other products the pharma industry is well-versed in producing.

Scientists design synthetic genetic material to deliver into patients, either via their own cells, benign viruses known as vectors or specially made bubbles of fat. Constructing these treatments is tricky even in a research setting, where small amounts of such material might be required for early experiments. But it's much harder for companies running clinical trials, or preparing for mass production.

Manufacturing delays can wreak havoc on young companies, causing them to miss milestones that could endanger future funding. Established gene therapy biotechs like UniQure or BioMarin Pharmaceuticals have spent years and millions of dollars to build their own plants. But startups and academic labs — where a number of the approved cell and gene therapies originated — can’t afford that.

“Academics have truly cutting-edge research, and I have been blown away by some of the creative ideas, novel modalities and breakthrough innovations that came about,” said Ran Zheng, the CEO of Landmark Bio, a Massachusetts-based company that caters to cell and gene therapy developers. “But that information needs to be translated into therapeutics, and this is the biggest, and probably the first, hurdle [startups] have to overcome.”

Turning to contract manufacturers like Thermo Fisher and Catalent can be a solution, but brings problems of its own. Transferring technology from a small lab to a larger organization can be arduous and require troubleshooting for glitches that arise in the process.

Big CDMOs may also prioritize more lucrative work with larger biotech and pharmaceutical firms. And they're struggling to meet the surging demand for cell and gene therapy manufacturing tools themselves.

Building up capabilities internally can be costly for startups. Viral vectors, for instance, are expensive to make and handle.

“You often see companies trying to own their own manufacturing and unfortunately, in this environment, if the product’s not successful, that's a heavy capital and operating expense to carry,” said Mike Paglia, a senior executive with ElevateBio, a richly funded startup that helps manufacture cell and gene therapies.

How are these startups trying to change that?

Rather than compete directly with larger CDMOs, some manufacturing startups aim to provide a more cost-efficient path for companies to develop in-house production capabilities. To appeal to younger biotechs that may need them, they are building relationships earlier and providing more services to attract first-time founders and small teams.

Many of these conversations take place long before an application to begin human testing, so these smaller manufacturers work to teach startups about raw material control strategies and set realistic timelines to gather early clinical data.

“Traditional CDMOs are like a kitchen, you'll give them a recipe and they make an entree,” said Zheng, who previously worked in manufacturing and operations at Orchard Therapeutics and Amgen. “That’s all they do. We're not like a kitchen where you just simply state the recipe. We actually ask our clients what ideas they have and we develop the recipe with them.”

Some clients start from near the beginning, working with these newer manufacturers from the moment they identify a lead candidate.

ElevateBio and Landmark Bio both help startups with laboratory studies to ensure that, down the line, they’re familiar with how to transfer their drugmaking technology to the companies that might eventually produce their therapies.

Paglia, who previously worked at Bluebird bio, said the biggest hurdle for him and his former colleagues was transferring their technology to contract manufacturers.

“Whether it was manufacturing our lentiviral vectors or cell therapy products, it took tremendous amounts of oversight to get those processes right because of the infancy of the industry,” he said.

Still, outsourcing to a dedicated manufacturer can save biotechs millions of dollars in the long term, Paglia said, allowing them to put that money toward additional clinical studies. That has meant steady demand for CDMOs, and created business for new startups trying to help.

Manufacturing startups have also attracted academics and nonprofits that struggled to get time with larger CDMOs. Landmark has worked with researchers who have received National Institutes of Health grants, for example.

Ultimately, improving manufacturing might give companies an opportunity to rethink how they price cell and gene therapies, which are some of the costliest medicines to make. The few companies that have reached market have noted these high costs in setting price tags that range from hundreds of thousands to millions of dollars.

Who are the startups in the space?

At least six biotech startups have launched since 2017 to address shortfalls in cell and gene therapy manufacturing.

The most richly funded, ElevateBio, has raised about $1.3 billion since it began working with drugmakers. It’s also spun out its own biotech startup with Boston Children’s Hospital to develop more convenient alternatives to current cancer cell therapies.

More recently, Ascend Cell & Gene Therapies in the U.K. emerged from stealth armed with $130 million in funding and led by industry veterans. It’s focused on adeno-associated viruses, a heavily used type of viral vector, and has acquired some of its capacity and technology from the struggling Freeline Therapeutics.

“AAV manufacturing is complex and needs teams that show real expertise and ownership,” said one of Ascend’s founding investors, Tim Funnell of Monograph Capital, in a statement on the company’s launch. “This led many advanced modality biotech developers to build their own internal CMC capabilities. However, these companies are now finding it difficult to sustain and fully utilize their facilities.”

There are smaller ventures, too. A pair of University of Pennsylvania researchers who worked on the cell therapy Kymriah and the gene therapies Zolgensma and Luxturna launched VintaBio in April. Months before in January, biotech startup creator Versant Ventures debuted Vector BioMed to help supply startups with the "lentiviral" vectors often used in ex vivo treatments.

What’s the status of their work?

With demand for more CDMOs at an all-time high, these startups are partnering with drugmakers straight out of the gate. Though many rely on capital infusions from venture firms, they also can generate cash from their work early on, bringing returns to investors well before a typical biotech might.

Landmark Bio had its first customer “even before we put a sign on the door,” Zheng said in October. In early June, it announced a partnership with InnDura, a new biotech company focused on “natural killer” cell research.

ElevateBio, having been around for some years, boasts a larger client list, noting in a May fundraising announcement that it added more than 15 new biopharmaceutical partners over the past year. Its subsidiary Life Edit Therapeutics is collaborating with large drugmakers like Novo Nordisk and Moderna.

VintaBio has a 22,500-square-foot facility in Philadelphia that’s now open for business, while Vector BioMed is working out of Gaithersburg, Maryland.

Shape Therapeutics is somewhat different, as it’s working on its own research, too. But it has also hinted at playing a manufacturing role, developing a new kind of cell line for producing adeno-associated viruses and indicating plans to build a factory where other companies can make their therapies.

CRISPR pioneer Feng Zhang is again making a mark in biotechnology, this time with a new startup focused on expanding the kinds of diseases genetic medicines can treat.

Aera Therapeutics officially debuted Feb. 16, announcing a combined Series A and B funding of $193 million. The company, which is headquartered in Boston, is formed around technology that’s meant to help solve one of genetic medicine’s most vexing challenges.

Gene therapy, which encompasses RNA-based medicines as well as gene replacement and gene editing applications, has been a hot area of research for biotech startups and pharmaceutical giants alike over the past decade, spurred by its potential to create powerful, long-lasting treatments for many diseases.

However, delivering gene therapies to the right area of the body for them to work remains a major obstacle. Infused genetic medicines are often limited to diseases of the liver, where they will usually end up, or to “ex vivo” applications, involving the modification of cells outside of the body.

Genetic medicines are also expensive to develop and manufacture, due in part to the high costs of the components that make them work, such as engineered viruses.

In 2021, Zhang's lab at the Broad Institute of MIT and Harvard identified a collection of proteins in the human genome that could form “capsid-like” structures capable of transporting genetic cargo within the body. One of the proteins, known as PEG10, could be engineered to "package, secrete and deliver specific RNAs," according to a Science journal article published that year.

He took that research to Bob Nelsen of Arch Venture Partners and Issi Rozen of GV, two investors with experience building gene editing companies. In September 2022, Zhang tapped former Alnylam Pharmaceuticals executive Akin Akinc to become Aera’s CEO and, more recently, longtime Alnylam leader John Maraganore to be its chairman.

The company isn’t yet working on building a pipeline of medicines, Akinc said. Instead, it’s first spending time developing its technology and identifying potential applications.

“The greatest unmet need today in terms of the genetic medicine space is delivery,” Akinc said in an interview with BioPharma Dive. “Ultimately, what we're after is a genetic medicine, and that means combining those two.”

Akinc claims Aera can address the safety and immunogenicity issues sometimes seen with current gene-based treatments. Aera is starting with human proteins, which its researchers hypothesize could lower the risk of provoking unwanted immune responses.

Cracking the code for delivery may also lead to new targets, perhaps in the central nervous system, heart or lungs, Akinc said. And it could also help with some of the problems associated with manufacturing the complex medicines.

“We’re less interested in trying to do a different way of solving a problem that's already been solved with lipid nanoparticles or viral vectors,” Akinc said, referring to the two most common ways to deliver genetic medicines.

Aera’s platform is built on work done in Zhang’s lab, where he also developed the research that led to the formation of Editas Medicine and Beam Therapeutics. Some of that technology also comes from a biotech it acquired called VNV, which Akinc described as doing “similar work” to Aera.

Arch and GV, which both bet big on gene editing company Prime Medicine, are joined by Lux Capital in leading Aera’s private financing rounds. The cash raised so far will be put to building out its team, currently numbering roughly 50 employees, Akinc said.

The company’s board of directors also includes Maraganore, former Vertex Pharmaceuticals president Vicki Sato and ex-Agios Pharmaceuticals CEO David Schenkein.

Maraganore, who advises several other biotechs, among them Beam and Orbital Therapeutics, said Aera’s technology could be “disruptive for the future of genetic medicine.”

“I'm trying to make new Alnylams, and companies like Orbital, Beam and Aera are great examples of companies I think have the potential to be the Alnylam of the future," Maraganore said.

A high-profile clinical trial testing Sarepta Therapeutics’ new gene therapy for Duchenne muscular dystrophy failed to meet its main goal, the biotechnology company said Oct. 30 in an update that calls into question the treatment’s future.

However, Sarepta, which has a history of back-and-forth interactions with regulators, claimed additional data from the study show a consistent benefit to treatment. The company has shared the results with the Food and Drug Administration and plans to ask the agency to expand its clearance of the therapy, which Sarepta sells as Elevidys.

The news comes four months after the FDA granted Elevidys accelerated approval in 4- and 5-year-old boys with Duchenne, an inherited disease that progressively weakens muscles. Sarepta’s trial, called EMBARK, was meant to confirm that approval by showing increased levels of a muscle-protecting protein translate to more definitive health benefits.

On the study’s main measure, a functional scale known as the North Star Ambulatory Assessment, trial participants treated with Elevidys improved by 2.6 points, compared to 1.9 points among those given placebo. The difference was not statistically significant, Sarepta said.

But on other measures, such as how quickly participants could rise or walk 10 meters, Elevidys appeared to help participants improve. Sarepta plans to share full study results at an upcoming medical meeting and publish them in a medical journal.

Typically, the FDA does not consider data on secondary study goals to be positive if the trial misses its primary endpoint. But it has taken a more flexible approach when diseases are severe, like Duchenne, and when patients have few good treatment options.

Doug Ingram, Sarepta’s CEO, told investors on an Oct. 30 call that the company views its data as showing Elevidys can change Duchenne’s course.

"Our goal is to expand the label to cover all amenable Duchenne patients without regard to age or ambulatory status,” said Ingram. “FDA leadership has also confirmed their goal of moving swiftly to review this new data and conclude its review on the label expansion, hence we will be moving rapidly to make a formal submission.”

Ingram added that Sarepta has already met with senior FDA officials, including Center for Biologics Evaluation and Resaerch Director Peter Marks, who previously intervened in the agency’s review of Elevidys, according to reporting from Stat.

“It was a very productive, very positive meeting,” Ingram said. “I want to be very clear: we still have a submission and a review to go through but I was very encouraged by the discussions with the agency.”

Sarepta studied Elevidys in boys with Duchenne between the ages of 4 and 7, and initially asked for approval in ambulatory indidviduals. But the data the biotech had marshalled in support were mixed and the agency ultimately decided on a compromise approval in only 4- and 5-year olds, for whom results appeared more positive.

EMBARK, which enrolled 125 boys with Duchenne, was therefore viewed as a way to expand Elevidys’ use to the older children who couldn’t access the treatment because of their age. As Duchenne is progressive, older boys tend to have lost more function that Elevidys would be unlikely to restore.

Data shared by Sarepta showed that on the NSAA scale the younger boys enrolled in the study appeared to do better than those who were older.

While about a third of trial participants experienced a side effect judged to be related to treatment, few were serious, Sarepta said. No one in the study discontinued and there were no deaths.

Roche, which paid Sarepta more than $1 billion to collaborate on Elevidys, took a more muted approach in its statement on the trial.

“High unmet need remains in Duchenne and we are encouraged by the consistent and meaningful results seen in all key secondary functional endpoints for Elevidys,” said Roche Chief Medical Officer Levi Garraway, in a statement. “We will work to further analyse the Embark results and consult with health authorities as quickly as possible.”

Under the companies’ alliance, Roche is responsible for regulatory reviews outside of the U.S., while Sarepta is in charge of discussions with the FDA.

Sarepta sells three other drugs for Duchenne, but their use is limited to certain groups of patients. Unlike those drugs, Elevidys is meant to be a one-time treatment that replaces the gene that’s damaged in people with Duchenne.

However, because of the size of that gene and how the therapy is delivered, Sarepta had to engineer a “mini” version of the gene, which produces a shortened form of the crucial dystrophin protein.

Gwendolyn Wu contributed reporting.

The Food and Drug Administration in late June approved the first gene therapy for the most common form of hemophilia, clearing the way for what patients, doctors and the medicine’s developer hope could be a one-time treatment for the rare bleeding disorder.

BioMarin Pharmaceutical, the California-based company behind the therapy, plans to sell it under the brand name Roctavian. It’s specifically meant to treat hemophilia A, which is caused by genetic mutations that inhibit the production of a key blood-clotting protein known as Factor VIII.

The company has set a list price of $2.9 million in the U.S., higher than the therapy’s cost in Europe, where it’s priced at about €1.5 million and has been approved since last August.

The FDA’s decision concludes a prolonged journey to the U.S. market for Roctavian. BioMarin originally filed an approval application at the end of 2019, supported by evidence from a large clinical trial that showed its therapy sharply reduced bleeding rates and the need for Factor VIII infusions in patients with severe hemophilia A.

In spite of these results, the agency unexpectedly rejected BioMarin’s application and asked the company to collect at least two years’ worth of data on each participant in that trial. Notably, the safety and long-term effectiveness of gene therapies have been a focal point for the FDA and other drug regulators. There’s also been signs that the effects of BioMarin’s therapy may wane with time.

BioMarin met this request, but late last year said the agency now also wanted to see three-year data. The company submitted those results shortly after, but, in order to allow enough time for a proper review, the FDA pushed back its review deadline to June 30.

With approval now in hand, BioMarin’s focus will turn to ensuring a successful launch of its therapy. Though the company has seven other marketed drugs, it hasn’t been profitable for most of its 26 years in operation. But analysts believe Roctavian could be the tipping point. Joseph Schwartz of SVB Securities has forecasted around $2.2 billion in peak annual sales.

BioMarin and other gene therapy developers have argued that, dosed just once, these treatments could be more cost-effective than regular Factor VIII replacements or newer, longer-acting medicines. Roche’s hemophilia A drug Hemlibra, for example, carries a list price of about half a million dollars, and has gained popularity because it can be administered as infrequently as once every four weeks.

BioMarin’s therapy won’t be available to all hemophilia A patients in the U.S., however. The FDA approved it only for patients with severe disease who test negative for a type of antibody that attacks the virus Roctavian uses to deliver its helpful genetic material into cells.

Previously, BioMarin estimated that about 20% of patients in the U.S and 30% globally would be ineligible for Roctavian because of these antibodies.

The FDA’s nod for Roctavian comes less than a year after the agency approved Hemgenix, the first gene therapy for the less common “B” form of hemophilia. It was developed by the Dutch biotech UniQure and is sold in the U.S. by CSL Behring, at a list price of $3.5 million.

People with the blood disorder sickle cell are anticipating the arrival of two gene therapies that could dramatically reshape their disease, potentially offering something approaching a cure.

Insurers, too, are preparing for the treatments, which are expected to carry price tags in the seven figures. While five other expensive gene therapies are already available in the U.S., sickle cell is far more prevalent than the inherited diseases they treat, affecting an estimated 100,000 people in the country. Many are covered through Medicaid, the federal insurance plan for people with limited income.

An experimental model proposed by the Centers for Medicare and Medicaid Services last week could help state agencies better afford those medicines, as well as offer a testing ground for payment schemes that could apply to other pricey gene therapies. Yet the timeline for its implementation might mean it comes after the first sickle cell gene therapies reach market.

“Sickle cell is a call to action,” said Michael Sherman, chief medical officer of Point32 Health, the parent company of Harvard Pilgrim Health Care and Tufts Health Plan.

“Without these kinds of models, we’re going to see access issues,” he added. “The Medicaid state agencies, like other parts of the financing system, were never designed with this sort of upfront shock.”

The gene therapy model is one of three pilot programs CMS will test in the coming years in response to an executive order from President Joe Biden directing the agency to find further ways to lower prescription drug costs. Administration officials described these programs as building on last year’s Inflation Reduction Act, which gave Medicare the authority to negotiate prices for a limited number of drugs.

Under the gene therapy model, state Medicaid agencies could delegate authority to CMS to coordinate multistate frameworks to pay for gene therapies based on how much patients benefit from treatment. In sickle cell, for example, payment could be contingent on whether patients remain free of the pain crises they regularly experience.

These types of payment schemes, typically known as outcomes-based arrangements, are already used in some cases for the currently available gene therapies. But budget limitations and federal price reporting requirements have limited their use within Medicaid, indirectly shaping how they’re designed for private insurers, too.

“There’s a lot of benefit, I think, to having both more of a centralized purchaser or negotiator across Medicaid programs … and having more centralized data collection,” said Stacie Dusetzina, a professor of health policy at Vanderbilt University Medical Center. “I think it also gives CMS a little bit of an upper hand at the negotiating table.”

Jeff Marrazzo, the former CEO of gene therapy developer Spark Therapeutics, agrees that a centralized approach in Medicaid could help.

“What I’ve observed is that state Medicaid agencies … generally have experienced more challenges with providing access to cell and gene therapies,” he wrote in an email. “This is due in part to the cost density of cell and gene therapies, but also because these organizations lack the infrastructure required to implement alternative pricing, reimbursement, and access models.”

Marrazzo cited data collection as one example, noting that some state agencies might lack the ability to appropriately track clinical outcomes for patients treated with a gene therapy.

CMS envisions testing several different types of outcomes-based arrangements, including an annuity model where continued payment is based on continued benefit. (To date, gene therapy developers have favored a rebate-based approach, where a certain percentage of their treatment’s cost is returned to the insurer if a specific outcome is not achieved.)

Five years ago, Spark proposed a similar annuity-based idea to help insurers pay for its then newly approved gene therapy Luxturna, for a type of childhood blindness. Spark priced the treatment at $425,000 per eye and sought to offer an installment payment plan, proposing the CMS run a demonstration project around Luxturna.

Its ability to do so was limited by Medicaid rules requiring drugmakers give the program the “best price” they offer on their products. In the event a patient didn’t benefit from treatment, and an insurer therefore didn’t owe the remaining installment payments, Spark would have had to report that fractional cost as its best price.

CMS recently tweaked its policy, allowing drugmakers to report multiple “best prices” in the context of outcomes-based arrangements. “This was an important first step,” Marrazzo wrote. “Along with the [recent] policy change, I do believe CMS providing a more centralized approach could lead to more annuity models being taken up, particularly by Medicaid plans.”

The agency plans to focus the model on a specific disease, and indicated sickle cell as a likely candidate. Behind the advancing sickle cell treatments is a growing pipeline of other gene therapies in development.

“Our concern has been that, for some of these more rare diseases, we haven't seen the access that we would like to see. Sickle cell is one of them,” said CMS Administrator Chiquita Brooks-LaSure on a call with reporters last week. “One of the reasons we're so excited about this model is because we think states need some assistance from us to really be effective in the space.”

But CMS doesn’t envision launching the gene therapy model until 2026 at the earliest, years after the two gene therapies now nearing market are expected to be approved. Their developers — Bluebird bio and partners Vertex Pharmaceuticals and CRISPR Therapeutics — are currently preparing approval applications that they expect to finish filing with the FDA this quarter.

Under current timelines, CMS would begin developing the model this year and announce model specifications in 2024 and 2025, with implementation following the year after. The agency would then track metrics like gene therapy spending, use and change in access over time to evaluate its success.

To some, earlier would be better. “Being in a business, I don’t understand why it takes two years to announce model specifications,” Sherman said.

The planned model is also voluntary, so CMS would need to rely on participation from both state Medicaid agencies and from drugmakers. The latter group, CMS argued in its report, would be enticed by the prospect of simpler market access.

That access could come with some tradeoffs, however. “It may be a little bit less attractive because of the inability to command the highest possible price, especially if there is a large population that's going to be treated and many Medicaid programs are interested in joining together into this kind of one model,” Dusetzina said.

As a top regulator at the Food and Drug Administration, Peter Marks isn’t responsible for weighing the cost of the treatments his teams review. But he is worried that some of the drug industry’s most promising medicines may not reach patients with uncommon diseases if companies can’t figure out how to sell them.

There are an estimated 7,000 rare diseases, many of which affect only small groups of people. Genetic medicines, including RNA-based drugs and gene replacement therapies, could offer a powerful way to treat, and potentially even cure, some of them. But for would-be developers, diseases affecting only a few dozen people might not represent a large enough market to justify the cost of developing and selling a new treatment.

“We're not going to find enough philanthropic groups to foot the bill for gene therapies for the hundreds upon hundreds of different diseases that need to be addressed,” said Marks, head of the FDA’s Center for Biologics Evaluation and Research, at a conference hosted by the Alliance for Regenerative Medicine on Oct. 12.

“We're gonna have to find a way to make this commercially viable so that industry can find a way forward towards this."

According to Marks, commercial viability for a gene therapy means administering roughly 100 to 200 treatments a year, a threshold that could be difficult to clear in a single country for rare conditions like severe combined immunodeficiences or adrenoleukodystrophies.

“It has not escaped our attention at FDA that there have been some clouds on the horizon in gene therapy,” said Marks, noting instances when gene therapies were taken off the market or returned by their developers to the original academic researchers.

In Europe, for example, first GSK and then Orchard Therapeutics abandoned one of the first gene therapies approved there, a treatment called Strimvelis for a condition known as ADA-SCID. Only a few dozen patients were ever treated, and Orchard has also handed back rights to a successor treatment. More recently, Bluebird bio withdrew two gene therapies from the EU market after running into difficulties securing reimbursement in several European countries.

Bluebird recently won FDA approval for both of those therapies in the U.S. One, to be sold as Skysona at a cost of $3 million, is for an inherited condition known as CALD that affects about 50 boys each year. Bluebird has said it expects to treat around 10 each year.

In his remarks to the conference, known as the Meeting on the Mesa and attended by many in the cell and gene therapy field, Marks highlighted a few areas where the FDA could help ease hurdles for ultra-rare disease treatments.

The agency is currently putting together a “cookbook” for developing and manufacturing of bespoke gene therapies, which could help academic groups more easily transfer treatments they’re working on to industry. It’s also looking into how to use non-clinical and manufacturing data from one application to speed the review of others that share similar technology.

“There are certain pieces of gene therapies that are not like your typical small molecule drug, because they're reused repeatedly,” Marks said.

Automated manufacturing could be another solution to help lower the costs of production, which are significantly higher for cell and gene therapies than for other more established drug types.

The FDA is also hoping to get on the same page with other regulators so that developers could be more confident a product they gain approval for in one country would have a good chance of success in others.

“Some of [these problems] may relate to how we can make gene therapies for small populations more widely available,” Marks said. “What may be a tiny population in the U.S. becomes a reasonable sized population when you go globally.”