What's going on with gene therapies? (Part one)
Cell and gene therapies are treating previously untreatable diseases and saving tens of thousands of lives. So why are companies shutting down?
First attempts in a new field of medicine rarely go according to plan. On September 14, 1990, Dr. William French Anderson and his team at the National Institute of Health (NIH) performed the first official gene therapy trial. The patient, a 4-year-old Ashanti deSilva, suffered from a rare genetic disease called adenosine deaminase (ADA) deficiency, a form of severe combined immune deficiency (SCID). Children with ADA-SCID rarely make it to adulthood; the lack of a functional immune system makes any illness potentially lethal. To make up for the deficiency of this crucial enzyme, Ashanti had been receiving ADA injections since she was two, but the effectiveness of this treatment usually declines fairly quickly, and by age four, she was no longer responding to it.
Ashanti’s parents, Raj and Van DeSilva, felt like they had run out of options for their daughter. They put all their hopes on this trial. Anderson and his team extracted white blood cells from Ashanti’s body, inserted a functional copy of the ADA gene into these cells using a retroviral vector, and then infused the genetically modified cells back into her body. Remarkably, this worked. Ashanti’s immune system function improved over the next few months; her T-cell count rose dramatically, and she no longer constantly fell sick. It was not a one-time cure — she still needed regular infusions every two months to maintain her health — but to her parents her recovery was nothing short of miraculous. Ashanti could begin living a normal life for the first time; going to school, for one, was no longer a life-threatening affair.
Thirty-five years since that first success, a very similar story swept the world. On May 15, 2025, Kyle Junior Muldoon — better known to the world as baby KJ — made headlines after the announcement that he had been successfully treated with the first personalized, CRISPR gene-editing therapy. Just nine months earlier, in August 2024, mere days after birth, KJ was diagnosed with carbamoyl phosphate synthetase 1 (CPS1) deficiency, an extremely rare and often fatal genetic disorder that prevents the body from breaking down ammonia. What followed was an extraordinary race to create a cure just for him: within days, his DNA was sequenced to find the specific mutations (two, in his case) in the CPS1 gene. Then, a cutting-edge base-editing therapy was designed tailored to these mutations. By months four and five, preclinical safety and efficacy testing was underway in mice and monkeys, and by month six, the FDA approved this single-patient product within a week of the application.
After receiving two infusions of his therapy — one in February 2025, and another a month or so later — he quickly began getting healthier. He could tolerate more protein, started gaining weight, needed fewer medications, and could achieve simple, regular baby activities, like sitting upright. On June 3rd, 2025, nine months after he was born, KJ was discharged from the Children’s Hospital of Philadelphia. His parents took him home for the first time.
These two extraordinary stories, three and a half decades apart, share a lot in common: parents grasping onto the last thread of hope for their child, the magical idea of fixing previously untreatable afflictions at the very core, teams working urgently for months to develop a cure, and, ultimately, a chance for a child to live a regular life.
But there are also some key differences that reflect the progress the field of cell and gene therapy has gone through in that time: new technologies, updated regulations, better development speed, safety, and efficacy, and a broader number of target diseases. Ashanti’s trial took two years of rigorous reviews from application to approval; KJ’s took two weeks. Ashanti’s therapy used a retroviral vector to deliver the functional gene, a delivery mechanism that would later be culprit in accidentally inserting genes away from its target (a possibly devastating outcome known as insertional mutagenesis). KJ’s, on the other hand, used lipid nanoparticles — these incredibly minuscule fat-bubble suitcases — to transport mRNA, which is then translated into a base-editor protein that edits — as if correcting a spelling in a word processor — only the specific mutation. Ashanti’s therapy was ex vivo: cells were extracted and modified outside the body; KJ’s therapy was in vivo: his body performed the modifications itself. Ashanti’s therapy was not personalized; the same product was used for all ADA-SCID patients. KJ’s was personalized to his exact mutation.
KJ’s story was celebrated across the world. This incredibly rapid, precise, effective therapeutic future should, after all, imbue a grand sense of excitement. His triumph over impending death is an astonishing demonstration of what 21st century medicine can achieve when cutting-edge science, experienced and compassionate medical staff, and proactive regulators come together, driven with a sense of urgency. These “elite institutions with complementary superpowers” — as Fyodor Urnav, Scientific Director at the Innovative Genomics Institute at UC Berkeley and one of the key characters in the baby KJ success story puts it — gave a boy with almost no hope, and his family, the chance at a regular life.
And yet, this triumph reveals a troubling paradox. We now find ourselves at an inflection point where the science to perform such miracles, to cure rare and even ultra-rare genetic diseases — like spinal muscular atrophy (SMA), hemophilia A, even restoring vision — is not only advancing rapidly but is demonstrably here. Regulatory pathways, like with the rapid approval for baby KJ, have even evolved to support these breakthroughs. But, despite saving many lives, many therapies born from these advances don’t ever get commercialized, and if they do, many are unable to translate into sustainable businesses.
So instead, we are seeing bankruptcies, downsizing, plummeting stock prices, and on-the-cheap acquisitions. Bluebird Bio, once a leader with three FDA-approved gene therapies, sold itself to private equity for around $30 million earlier this year, a 99.7% decline from their all-time-high $10b valuation. In February this year, Pfizer abandoned Beqvez, its FDA-approved hemophilia B gene therapy, citing “limited patient and physician interest”, and effectively exiting the gene therapy field altogether. Editas and Beam, two highly-acclaimed public companies in the gene-editing space, have seen their share prices plummet by 90% since their 2021 all-time highs. These troubling commercial and financial setbacks are scaring away the crucial investment needed for developing future cures or commercializing existing ones.
This is the tragedy-to-be: science and technology offer a cure, but we risk a future where these life-saving treatments remain undeveloped or inaccessible, simply because we haven't yet built a system that can support them. In economic terms: cell and gene therapies suffer from a market failure.
The immediate question is: why? Why aren’t cell and gene therapies — evidently capable of miraculous cures — turning into successful businesses? What are the factors that prevent these products from escaping the “valley of death” — flourishing beyond the initial scientific breakthrough or successful clinical trials? Answering that might give us hints at asking the larger questions. How might we fix it? What might a system that incentivizes these rare-disease therapies look like? What are the regulations and funding models — designed for a world of off-the-shelf, repeated use medicine — that can support developing personalized therapies? And most importantly, how can we deploy these life-saving technologies to the people that need it?
Perhaps these questions surrounding the science, the treatment, the regulations, and the economics are best illustrated with an example. After going through multiple FDA programs — Fast Track, Orphan Drug, RMAT, and a Rare Pediatric Disease priority review voucher — in January 2024, Casgevy became the first FDA-approved gene therapy that uses CRISPR-Cas9. It is a treatment for sickle-cell disease and beta thalassemia, diseases caused by a genetic defect that produces hemoglobin — the shipping-container-like protein in red blood cells that ferry oxygen across the body — with an irregular shape (sickle-shaped, giving SCD its name) or in insufficient amounts (beta thalassemia).
The treatment is ingenious, and makes use of one of the wonders of the human body. Before birth, fetuses in the womb use fetal hemoglobin to ferry oxygen across the body. After birth, the fetal hemoglobin gene is turned off, and replaced by adult hemoglobin. Since patients with SCD have deformed adult hemoglobin, one possible option was reactivating fetal hemoglobin instead. Casgevy works by extracting blood stem cells from bone marrow, knocking off the regulator that has switched off fetal hemoglobin production, and then infusing the stem cells back in the patient. The restarted production of fetal hemoglobin compensates for the faultiness of the adult ones.
This isn’t a complete cure, but it significantly reduces painful episodes (the sickle-shaped red blood cells can get stuck in capillaries, causing intense pain known as a vaso-occlusive crisis) as well as the need for blood transfusions. And, since it’s a single treatment that uses the patient’s own cells, there’s no risk of graft-versus-host disease — that terrible affliction where donor immune cells attack the recipient — and no repeated need for immunosuppressants.
For nearly every patient that has received it, Casgevy has been an enormous success. In the final clinical trials before approval, over 100 patients had been treated. For sickle-cell disease, among patients with at least 16 months of follow up, 92% (36 of 39) were free of vaso-occlusive crises for at least 12 consecutive months. For beta thalassemia, 94% (49 of 52) didn’t require a blood transfusion for at least 12 consecutive months. Early data tracking post-approval treatments had similar rates for the same outcomes.
Jimi Olaghere, a young Atlanta resident, was one of the patients enrolled in these trials. He shared his experience with Casgevy in an op-ed for MIT Tech Review: “I started to experience things I had only dreamed of: boundless energy and the ability to recover by merely sleeping. [...] I gained the confidence that sickle-cell disease won’t take me away from my family, and a sense of control over my own destiny.”
For patients like Jimi, this potentially curative, one-time infusion of their own, edited cells allowed them the chance to live a more regular life. But there’s a catch, and a little more to this tale.
For one, Casgevy has an incredibly high price. The one-time treatment is set at $2.2 million, and this doesn’t include additional expenses such as pre-treatment evaluation, the hospital stay for stem-cell collection, and any follow-up care.
If one does decide to go ahead with the treatment, the entire process is gruelling, and can take up to 5-6 months. First, the patient is evaluated — screened for infections and certain medications — at an authorized treatment center. Then, the patient receives medications to mobilize hematopoietic (blood) stem cells from the bone marrow into the bloodstream. Over the next few days, blood is repeatedly drawn out and the specific stem cells needed — CD34+ cells — are separated and collected, which is then shipped in a sterile bag to a specialized manufacturing facility. There, the cells are further purified and exposed to the CRISPR-Cas9 gene-editing complex through electroporation, a process where an electric pulse opens up the pores in the stem cell membrane, allowing the molecular complex to enter. One inside, the CRISPR-Cas9 targets and edits a specific region of the BCL11A gene, which reduces the gene’s expression, and in turn, increases the production of fetal hemoglobin (once inside the body).
These modified stem cells are then mixed with a cryopreservative solution and frozen in liquid nitrogen for storage. A small sample undergoes extensive testing for viability, purity, potency, sterility, and safety, which can take months since the cells need to be cultured. Once all the tests have passed, the final product is transported in a special cryoshipper back to the treatment center.
Before receiving their edited cells, the patient has to undergo chemotherapy to clear out their existing bone marrow cells. Once depleted, the modified stem cells are thawed and infused into the patient’s bloodstream, and they’re kept in the hospital until their new cells engraft and their blood count recovers.
This entire Casgevy process illuminates why such a therapy can be so expensive. It requires a phenomenal amount of resources: specially trained medical staff, temperature-controlled transportation, sophisticated gene-editing capabilities, and comprehensive safety checks. There are no economies of scale; each patient’s therapy is a separate campaign. And there are clear bottle-necks and failure points. Cells begin deteriorating within hours of collection and degrade rapidly if temperature deviates during transport (it needs to be kept at 2-8°C for unedited cells; -150°C for edited cells). And a significant chunk of time is spent waiting for the stem cells to culture during testing. A single misstep or accident could undo months of progress.
This operational complexity and fragility makes providing Casgevy a difficult business to operate and scale. Despite their clinical successes and blockbuster announcement, sales figures in the last quarter of 2024 and first quarter of 2025 have fallen short of analyst expectations1.
The need for specialized treatment centers and specially-trained staff were two key reasons cited for their lagging pace. Another one was simply the slow uptake of patients. Even after regulatory approval, it took many months before the first patients were treated; ten months after approval, only eight patients had completed treatment (although 90 had started the collection process). The high price poses a major barrier to patients — insurers are cautious about paying, often requiring complex negotiations, outcomes-based agreements, or risk-sharing models before agreeing. And, despite the clinical trial successes, it can be easy to forget that this is still a difficult, medically intensive journey for the patient, requiring chemotherapy, hospitalization, and months of recovery. Along with complex manufacturing, these patient-specific factors — eligibility, willingness, location — and a complex reimbursement landscape make it hard to predict revenue. Thus, despite being a breakthrough product, the path to profitability for Casgevy seems uncertain.
These “bench to bedside” hurdles are not unique to Casgevy. Many FDA-approved cell and gene therapies have similar operations and scaling hurdles. All seven cancer-fighting CAR-T therapies, which include Yescarta for B-cell lymphoma and Kymriah for acute lymphoblastic leukemia (ALL), require similar steps — collect T-cells, modify with vectors, multiply, and reinfuse — and thus potentially have the same scaling drawbacks. As do the two other therapy options for sickle-cell disease and beta thalassemia — Lyfgenia and Zynteglo, respectively — just swapping CRISPR with a lentiviral vector. Typically, it’s the allogenic options — cells taken from donors — that skip the collection and gene editing or delivery steps, but it has other drawbacks of its own, like donor-patient matching, and, of course, are not personalized.
Operational complexities, multi-million-dollar price tags, challenging reimbursement landscapes, and a slow and uncertain path to commercial viability represent systemic issues that threaten the broader promise of cell and gene therapies. But the problems identified also hint at possible solutions. From the Casgevy example, we can garner three primary headwinds: manufacturing hurdles, cooling investment, and reimbursement struggles. In Part Two, we’ll take a closer look at these three facets for the industry as a whole. Then, we’ll explore some potential solutions that either fix the issue directly, or jump past it altogether, particularly those brought up in the June 5, 2025, FDA Roundtable on Cell and Gene Therapy.
Although Vertex Pharmaceuticals expects sales to increase once new treatment centers are up and running
Maybe of interest on this topic: https://norn.group/writing/gene-therapy-for-common-diseases