This past spring, a biotech company announced the first use of a new gene-editing technology in people to fix an errant gene that causes a severe immune disorder. In June, a baby born with a life-threatening metabolic disorder was allowed to leave the hospital after a six-month sprint by scientists to create a bespoke treatment for him. And increasingly, a generation of “bubble babies” born without immune defenses are nearing their teenage years after receiving a one-time experimental gene therapy in early childhood.
Therapies that target genetic illnesses at their root are no longer on the horizon. They are here. More are coming. But even as a growing suite of gene therapy tools are changing individual patients’ lives, many are getting stuck in a medical purgatory because they don’t fit the model for turning breakthroughs into accessible treatments.
Donald Kohn, a pediatric bone marrow transplant physician at the University of California at Los Angeles, has successfully rebuilt children’s immune systems with gene therapy in the clinic for over a decade, but it has not yet become a medicine.
“There are several dozen rare diseases in a similar situation, where there is a therapy that looks good in academic clinical trials. But getting to the end zone of an approved drug is very challenging,” Kohn said.
The potential public health impact may appear small individually, but it is massive collectively. Rare diseases are estimated to afflict 300 million people globally, and around 70% of them trace to genetic causes.
Typically, drug development is a relay race. Academic labs, backed by federal funding, often do the early, basic research. Companies run the next leg to turn those insights into drugs. While scientists can now utilize an expanding arsenal of gene therapy technologies to start the race against potentially thousands of diseases, finding someone to pick up the baton is challenging when any individual therapy may help a handful of patients ― or even just one.
That limbo has led scientists to experiment with new business models and more efficient ways of testing new therapies to fill a market gap. They are building biotech companies that don’t rely on maximizing profits, launching nonprofits, and fashioning new kinds of clinical trials. The Trump administration has also weighed in to help.
In November, the Food and Drug Administration outlined a path forward for getting certain treatments of rare diseases with a clear biological cause to market.
“Unfortunately, FDA has heard from patients, parents, researchers, clinicians, and developers, that current regulations are onerous, unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view,” top FDA officials wrote in the New England Journal of Medicine. “Nearly 30 years after the sequencing of the human genome, bespoke therapies are close to reality.”
Lifesaving cures that ‘ebb and flow’
For several decades, scientists have tried to use cell and gene therapies to fix illnesses at their roots. A few dozen have been approved for diseases, such as sickle cell anemia and spinal muscular atrophy. Even as new tools have expanded this potential over the last decade, risks also exist. Patients have died after receiving gene therapies, showing the tension between encouraging innovation and guarding patient safety.
Perhaps no case highlights the opportunity — and the challenge — better than an experimental gene therapy designed to rebuild the immune systems of babies who were born without one. The disease, called severe combined immunodeficiency (SCID), has more than a dozen different genetic causes, but the same result: Babies are born without immune defenses.
The condition is rare, affecting 40 to 80 children in the United States each year, but was popularized by the story of David Vetter, featured in the 1976 movie The Boy in the Plastic Bubble.
In 2014, Jeffrey and Caroline Nachem’s newborn daughter, Eliana, developed a cough that wouldn’t go away. A blood test delivered a shocking result — a white blood cell count so low that the doctor ordered it to be run again, thinking it might be a fluke.
It wasn’t. The Nachems learned their daughter had a subtype called adenosine deaminase deficiency-SCID (ADA-SCID). They lived in Fredericksburg, Va., near the woods, but couldn’t open the windows because mold spores could float in. They found new homes for their pets. They wiped down every surface and changed clothes after coming home from the outside world, to protect Eliana from germs.
With a matched bone marrow transplant, the disease can be effectively treated, but the best option is from a sibling, and Eliana was the Nachem’s first child. Scientists had been developing gene therapies that turn a patient’s own cells into a possible cure, requiring a lower dose of chemotherapy and fewer immune-related complications.
Researchers remove bone marrow cells, use a harmless virus to insert a corrected version of the ADA gene, and then reinfuse the cells. At 10 months old, Eliana received an experimental gene therapy — and it worked. As her immune system rebuilt itself, doctors gave her parents the clearance to give her a kiss or bring her outside. When she was 18 months, the Nachems pushed her around in a shopping cart at the grocery store.
In a recent study in the New England Journal of Medicine, Kohn and colleagues reported the long-term follow-up of 62 children with ADA-SCID who were treated with a one-time gene therapy, including Eliana. Nearly all of them have had their immune systems fully rebuilt, going strong after an average of nearly eight years.
Eliana is now in sixth grade. “She is incredible. She has attitude, she is artistic, she is the commander of the world. Nothing gets in her way,” Caroline Nachem said.
The therapy, however, has been stuck.
A biotechnology company, Orchard Therapeutics launched a plan to develop the therapy in 2016, but stopped investing in it a few years later. Orchard returned the therapy to its academic inventors in 2022.
Researchers in Kohn’s lab spun out Rarity Public Benefit Corporation to turn it into a medicine. Now the bottleneck is developing the commercial manufacturing.
“I saw the ebb and flow of this therapy,” said Paul Ayoub, chief executive of Rarity. “The therapies work, but they stop at this academic stage … We wanted to put it in our own hands — take the proven science to the finish line.”
Meanwhile, families are waiting. Maria Thianthong, who lives in Los Angeles, is one of them. Her 3-year-old daughter, Eliyah, has been on the waiting list for the therapy since birth. Children with this form of SCID can live with injections of a replacement enzyme therapy, though it is considered a stopgap.
“Three years is a lot of time for them to figure out something with the funding,” Maria said. “We’re just a little impatient.”
A new era of ‘genetic surgery’
For scientists, the SCID example is a gold standard, but also a cautionary tale.
Running a trial with dozens of patients for a decade is a “Herculean effort” said Kiran Musunuru, a cardiologist at the University of Pennsylvania’s Perelman School of Medicine. He hopes that federal rules can be streamlined to speed up the process. Otherwise, many cures may never be made.
The beauty of modern gene-editing tools, many of which build off the Nobel Prize-winning CRISPR technology, is that cures become programmable. Instead of inventing a new medicine for each disease, scientists in theory can write a bit of code to address a patient’s unique mutation for multiple diseases.
David Liu, a biochemist at the Broad Institute and one of the field’s leaders, recently showed that a one-size-fits-all therapy could, with a single edit, treat multiple diseases in human cell and mouse models of disease. He’s also working with colleagues to create a nonprofit Center for Genetic Surgery to advance cures “that are not likely to be served by industry anytime soon, because their disease is so rare.”
A company he co-founded, Prime Medicine, announced promising early results last year in treating two patients with a rare, inherited immune deficiency called chronic granulomatous disease. But it announced that it would deprioritize the program to focus on other diseases.
The company is continuing to explore possible paths to federal approval with the current data set, rather than treating more patients.
Paving the way for the future is the case of “Baby KJ” Muldoon, an infant who received a custom gene-editing therapy for a rare metabolic disorder last year at Children’s Hospital of Philadelphia.
KJ celebrated his first birthday at home this summer, is learning to walk and is meeting developmental milestones. But he is one patient. Other children also suffer from similar disorders, called urea cycle disorders, that are caused by different mutations in multiple different genes. KJ’s treatment team is working on an “umbrella” clinical trial, in which five other children will be treated. They’ll use the same basic approach they used for KJ, but tailor the treatment to different genes and mutations.
The hope is the evidence, pooled together, could be used to support the treatment’s approval. Musunuru’s team recently published a step-by-step guide to their interactions with regulators in the American Journal of Human Genetics. He and other researchers, who have been encouraged by the FDA’s recent announcement about a new pathway, await more specific guidance on how it would operate.
“We’re kind of taking the stance, there are many patients like KJ who need therapies now,” Musunuru said. “The clock is ticking and we know we can do it now.”
