Precision gene-editing progresses, despite challenges

In 2023, the first CRISPR–(Cas9)-based product was approved by the US Food and Drug Administration (FDA): Vertex/CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel) for sickle cell disease (SCD) and beta-thalassemia. The approval was a landmark in the quest to design gene-editing therapies with curative potential. Casgevy shows exceptional efficacy, but so far the therapy has been administered to only a small number of the patients that could benefit from it.

One factor limiting Casgevy’s uptake has been the complexity and cost of the treatment process. Hematopoietic stem cells are collected from each patient, and edited ex vivo to produce therapeutic levels of fetal hemoglobin, which helps compensate for faulty adult hemoglobin. The edited cells are then re-infused, but patients must first undergo a demanding chemotherapy regimen to clear out existing blood stem cells and reduce rejection risk.

Several next-generation product candidates use in vivo gene editing, rather than ex vivo modification, potentially reducing the treatment administration burden. For example, in January 2025, Intellia Therapeutics began a phase 3 trial of its hereditary angioedema (HAE) candidate NTLA-2002, which uses CRISPR technology to knock-out a gene encoding a protein involved in HAE attacks. The therapy is delivered systemically using lipid nanoparticles (LNPs). The same month, Vertex paid $65 million up-front to access Orna Therapeutics’ proprietary LNPs as part of a three-year collaboration aimed at building an improved Casgevy.

Gene-editing methods are also being refined. Beam Therapeutics is using LNP-mediated in vivo delivery, but in this case the therapy involves editing a single nucleotide base, rather than breaking double-stranded DNA, as occurs with Casgevy and NTLA-2002. Base editing may mitigate potential risks that accompany double-stranded breaks, such as aberrant insertions or deletions at the break-site. Beam reported positive clinical data for its in vivo base-editing treatment BEAM-302 for patients with the rare lung disease alpha-1-antitrypsin deficiency in March 2025, providing proof-of-concept for the approach.

Other groups promise an even wider range of more precise gene-editing tools. Prime Medicine’s platform offers base-pair and DNA sequence edits, including to regulatory genes, while Tessera Therapeutics claims to be able to ‘write’ entirely new genes, as well as correcting existing ones. Companies are experimenting with nucleases beyond Cas9 and finding ways to deliver gene-editing therapies to a wider range of target organs.

Despite this progress, Intellia, CRISPR Therapeutics and several other gene-editing biotechs are having to cut staff and programs to preserve the cash required to get lead assets over the finish line. Beam shares fell after its data announcement, scuppering the biotech’s planned stock offering. Tome Biosciences, which debuted in late 2023 with over $200 million for a platform designed to precisely insert larger DNA sequences into the genome, has since gone out of business.

“The biggest problem is access to capital,” said Keith Gottesdiener, president and CEO of Prime Medicine, speaking at an Endpoints webinar in March 2025.

Some investors in today’s uncertain world lack the appetite for such risky, early-stage platform technologies. They are also wary of the high-priced products that result. At a time when common conditions like obesity, liver disease and psychiatric disorders have come into focus, gene-edited medicines for less-prevalent conditions (along with other cell- and gene-based therapies) look relatively unattractive. They may be the products of tomorrow, but today’s health systems do not easily support their price-tags and complex administration requirements.

Venture-funding trends

Data from DealForma show that just $280 million of venture capital (VC) dollars went into gene-editing biotechs in 2024 (Fig. 1a), about 1% of sector VC totals—and less than the single, $300 million+ Series C mega-raise by Tessera in late 2022. Only two of the seven VC funding rounds in 2024 were specified as seed or Series As; three were for Chinese companies, a reminder of the country’s growing role in innovation (Table 1).

There are silver linings in 2024’s figures. The average financing round size for gene-editing companies, at $68 million, was second only to companies developing more established classes of biologic medicines such as monoclonal antibodies (Fig. 1a).

The start of 2025 also brought better news for gene-editing start-ups. Light Horse Therapeutics emerged from Versant Ventures’ discovery engine with a $62 million Series A round, and Tune Therapeutics raised $175 million in a B round led by New Enterprise Associates. Together these two rounds alone eclipse the total VC funding for gene-editing in 2024.

Tune has initiated a phase 1b trial of its candidate Tune-401 for hepatitis B virus (HBV) infection. The therapy epigenetically silences both viral DNA integrated into the host genome, and viral episomes that generate new viral particles and sustain chronic infection, potentially providing a lasting functional cure.

Cancer-focused Light Horse, meanwhile, uses precision gene-editing not to make therapies directly, but as a tool to identify disease targets that are tractable for small molecules. The start-up announced a licensing deal with Novartis, worth $25 million up-front, on the same day as its Series A funding (Table 2).

Drilling into the deals

Overall dealmaking statistics from last year reflect a still-emerging sector yet to find widespread favor. According to DealForma, there were just eight research and development (R&D) partnerships (Table 2) and two mergers and acquisitions (M&A) deals among gene-editing companies in 2024, and one of the M&A deals involved the now-defunct Tome Biosciences. The total deal value in both categories was just a fraction of those across most other modalities, including cell therapy, which is also struggling. The median up-front value for gene-editing-focused R&D partnerships—$75 million—was strong relative to other areas, however (Fig. 1b).

While small deal numbers make it hard to draw firm conclusions from transaction values, there’s little doubt that gene-editing companies are not getting the dollars they deserve due to bad timing: these tools are emerging during an exceptionally long-lasting biotech down-cycle, drawn out by wider global factors—including US policy shifts and health department staff cuts.

Nevertheless, a look at the recent deals highlights the advances likely to sustain the field longer-term. One of 2024’s richest gene-editing-focused R&D deals was Regeneron’s $100 million up-front cash and equity investment into Mammoth Biosciences as part of a deal that could also be worth up to $370 million in milestones per target for Mammoth (Table 2).

There are two innovations here. Most in vivo gene therapies, including gene-editing therapies, target the liver, given its physiological role, the number of liver-expressed proteins that are linked to disease and the efficient hepatic uptake of delivery vehicles such as adeno-associated viruses (AAVs) and lipid nanoparticles (LNPs). Mammoth’s platform is designed to target non-liver cells, potentially addressing a wider range of conditions. Earlier this year, Mammoth shared preclinical research demonstrating that its platform can successfully edit muscle tissue, in vivo, using a single AAV vector.

Another innovation lies in the editing enzyme. First-generation CRISPR systems using the Cas9 enzyme are too large to deliver to the body using a single AAV vector, so Mammoth has designed a NanoCas editing enzyme only about a third of the size of Cas9 that fits in a single AAV. Indeed, it is so small that there is also room for other editing tools, which could enable even more intricate gene editing.

Editas Medicine’s October 2024 deal with Genevant Sciences, worth up to $238 million, and Intellia Therapeutics’ deal with ReCode in cystic fibrosis in February the same year (Table 2) followed a similar template: combining one partner’s editing tools with another’s delivery platform. Editas will twin Genevant’s LNP technology with its own CRISPR-based editing tool that uses Cas12a, a smaller enzyme than Cas9, against two undisclosed targets.

Outside CRISPR-based editing, the licensing deal between Roche’s Genentech subsidiary and Sangamo Therapeutics in August 2024 reflects neuroscience’s newfound popularity. Genentech paid $50 million up-front for rights to use Sangamo’s zinc-finger-based gene-tuning tools and a proprietary neurotropic AAV delivery vector to target and repress the microtubule-associated protein tau (MAPT) gene, which is implicated in Alzheimer’s disease, and a second undisclosed neurology target (Table 2).

Thirty-year-old Sangamo’s zinc-finger platform predates those from CRISPR companies by more than a decade, and while zinc fingers fell out of favor with the emergence of CRISPR, the company has persisted. In-house, Sangamo is developing a zinc-finger repressor targeting the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene that encodes the Nav1.7 sodium channel, which is implicated in chronic neuropathic pain. A phase 1/2 trial of the candidate (ST-503), in idiopathic small-fiber neuropathy is expected to start in 2025.

Other gene-editing deals have consolidated editing tools under one roof. Arbor Biotechnologies’ acquisition of Serendipity in May 2024 hauled in new families of compact, CRISPR-related gene-editing enzymes, including some that nick just a single DNA strand or allow sequence insertions; both companies were founded or co-founded by CRISPR pioneer and Massachusetts Institute of Technology (MIT) scientist Feng Zhang; no financials were disclosed for the deal.

Outlook uncertain

With just one marketed product and plenty of scientific and regulatory uncertainties for next-generation products, the gene-editing field looks particularly vulnerable to the prolonged biotech downturn. Even well-capitalized biotechs like Tessera may soon run out of road.

That biotech in late 2024 announced investments of up to $50 million from the Bill & Melinda Gates foundation for its in vivo genetic therapy for SCD, which could provide an alternative to Casgevy that is less complex and burdensome to administer. The approach involves using LNPs to deliver an editing tool that ‘writes’ a correction of the SCD mutation to patients’ hematopoietic stem cells via a one-time intravenous administration, skipping the stem-cell harvesting needed for ex vivo editing and the subsequent chemotherapy conditioning.

That program is still preclinical. But the financing hints that the gene-editing money—when it comes—will be directed toward individual assets offering greater efficiency, lower cost, and less patient burden than existing medicines.

Regulators have been on-side. The FDA has tried to expedite gene therapy and related new technologies, particularly those aimed at rare disorders with few or no alternatives. Efforts were underway to develop a modular approach to regulation, leveraging the common components shared by some gene-editing medicines. With sufficient evidence available on such components, regulators could potentially consider them suitable for use in new candidates aiming to enter clinical trials. The idea was that companies could then potentially tweak the parts that change—the guide RNA and other mutation-specific elements—with limited additional regulatory requirements before an investigational new drug (IND) application was approved. “We could file an IND for multiple diseases, which helps move the needle on [patient] access,” said Gottesdiener on the Endpoints webinar.

But that modular approach was not yet in place when President Trump’s team took over. Now, with swingeing cuts and changes across the FDA and other health agencies, this and other programs to expedite access to complex gene- and cell-based medicines may be at risk. The pre-Trump FDA had long recognized the need for more affordable, accessible gene-based medicines: products like Casgevy “are amazing, but they are generation one,” noted Peter Marks, then head of the FDA’s Center for Biologics Evaluation and Research (CBER), at a conference in late 2024. “We need to get to [generations] two and three that are easier to administer, and cheaper.”

In what appeared a severe blow to genetic medicines, Marks resigned from the FDA in March 2025. He had warned, in 2024, that gene therapy and related technologies were at “a tender moment,” and that abandoning these paths to faster approval and access could result in “a years-long set-back.” Marks’ exit, following those of several other senior figures within the FDA drug-approvals divisions, removes decades’ worth of experience. There have been positive comments from new FDA commissioner Martin Makary and from US Department of Health and Human Services chief Robert Kennedy Jr on the value of advanced technologies such as gene-edited medicines in offering cures for serious diseases. But at this early stage in the new administration, forecasting the FDA’s direction-of-travel is almost impossible.

Meanwhile, “the real boundary is not the [gene-editing] technologies; it’s our ability to use them in a way that benefits as many patients as possible,” said Broad Institute of MIT and Harvard professor David Liu, an inventor of base- and prime-editing innovations, in April 2025 after being awarded a Breakthrough Prize for life sciences. For now, such prizes aren’t enough to turn investors. But given exciting scientific advances—and a community focused on creative ways of getting gene-edited therapies to patients—the funding shall surely return.