For a child born with a devastating genetic disease, the scientific solution may already be imaginable: identify the single DNA error causing the illness and design a treatment to correct it.
Imaginable, unfortunately, is not the same as available.
Developing a genetic medicine traditionally takes years, costs enormous sums, and requires a separate manufacturing and clinical-trial process to evaluate safely for nearly every disease. For children with rapidly progressing conditions, some of whom may have only months before irreversible damage occurs, that timeline can make a promising treatment effectively unreachable.
A new federal program is attempting to change that model, and two Stanford Medicine teams are contributing distinct pieces of the solution.
The Advanced Research Projects Agency for Health, or ARPA-H, has committed up to $160 million over five years to its THRIVE program, an ambitious effort to make personalized genetic treatments faster, more affordable, and easier to adapt across multiple rare diseases.
One Stanford team is helping researchers identify children with rare immune disorders before they are born. Another, led by Stanford dermatologists, is developing a topical CRISPR treatment for children whose skin can blister from the slightest touch.
Starting the treatment clock before birth
Several thousand newborns in the United States are born each year with inherited disorders that prevent the immune system from functioning properly. Known as inborn errors of immunity, these conditions can leave children dangerously vulnerable to infections that most fight off easily.
Scientists know of roughly 500 such disorders. Yet only two currently have approved genetic therapies, each costing more than $1 million per child and requiring extensive hospitalization, according to the project team.
The new AEGIS project, short for Affordable Gene Editing Therapies for Immune System Diseases of Children, aims to create a faster and more scalable alternative. Led by the Innovative Genomics Institute at the University of California, Berkeley, the collaboration brings together specialists in pediatrics, immunology, gene editing, drug delivery, manufacturing, and clinical trials from institutions across the country. The Stanford Department of Medicine’s Big Ideas in Medicine program proudly supported the proposal-development process for Stanford’s participation in the project.
Stanford’s role begins at an unusually early point in a patient’s life: pregnancy.
A team led by Euan Ashley, MB ChB, DPhil, chair of the Stanford Department of Medicine, is developing sensitive, noninvasive methods to identify babies who may have an inherited immune disorder before they are born.
The team's approach takes advantage of a biological clue already circulating in the mother’s bloodstream: small fragments of the baby’s DNA. “Telling the two apart is a challenge because they’re nearly identical and the baby’s share is small,” says Matthew Neu, MD, PhD, a postdoctoral scholar in Ashley’s lab who is working on the early-detection technology.
To help make that distinction, the researchers also sequence the father’s DNA. If a genetic variant appears in the maternal blood sample and is present in the father but not the mother, researchers know that DNA must have come from the baby. “Our hope is that combining these clues gives a broader and more accurate picture of the baby’s DNA from a simple blood draw,” Neu says.
Why identify the disorder so early? For some severe immune diseases, the period shortly after birth may offer a narrow opportunity to intervene before a child becomes seriously ill.
“Pregnancy is an under-utilized diagnostic opportunity for genetic disorders,” says Christy Tise, MD, PhD, a pediatric geneticist working on the project. “Because the window of greatest benefit for treating severe immune disorders opens shortly after birth and can be quite short, knowing the exact disease-causing genetic change before birth allows safety testing and logistical planning to happen ahead of time.”
If researchers can identify the disease-causing genetic change months before delivery, they could use the remainder of the pregnancy to design and test the personalized component of a CRISPR treatment. “We envision beginning that process around 20 weeks before birth, with the goal of having the treatment’s customized genetic instructions ready soon after the baby arrives,” Ashley explains.
The broader AEGIS team plans to treat 10 children over five years, with the goal of reducing the time required to develop each personalized editor to less than three months and its cost to below $200,000.
The treatment is also designed to simplify how gene editing reaches the patient. Many current genetic treatments for blood and immune diseases require physicians to remove a patient’s stem cells, modify them in a laboratory, and return them after chemotherapy. AEGIS researchers instead hope to deliver the gene-editing machinery directly to stem cells in the bone marrow using an injection of specially engineered lipid nanoparticles, tiny fat-based particles that carry the treatment.
The approach remains experimental, and significant scientific and regulatory challenges remain. But the idea is straightforward: diagnose earlier, use that time to prepare the treatment, and deliver it directly to the cells that need it.
A spray-on gene treatment for fragile skin
Epidermolysis bullosa, or EB, is a collection of inherited diseases that leave the skin extraordinarily fragile.
Even minor friction or everyday contact can cause the layers of the skin to separate, resulting in blisters that can become large, painful wounds that persist for years. Patients also face infections, scarring, disability, and an increased risk of aggressive skin cancer.
A Stanford team led by Jean Tang, MD, PhD, and Anthony Oro, MD, PhD, has received an award of up to $26 million through THRIVE to develop NueSKIN, a topical gene-editing treatment that could be sprayed directly onto patients’ wounds.
NueSKIN builds on more than two decades of Stanford research into gene therapies for EB, including genetically corrected skin grafts made from patients’ own cells and a gene therapy gel applied to wounds. NueSKIN takes a different approach: using CRISPR to directly correct the genetic mutation causing the disease in a patient’s skin cells.
The goal, Tang says, is to give patients “a chance for permanent genetic correction after one treatment.” Because CRISPR-based treatments may also be easier and less expensive to manufacture than viral gene therapies, she says, “the approach could offer a more scalable and affordable path to genetic medicine.”
Each generation of treatment has helped inform the next, Oro says. “We have learned that to create a ‘definitive, one-and-done therapy,’ we have to be able to correct the disease-causing variant in the small numbers of skin stem cells that can continuously repopulate the skin,” he says. “The NueSKIN project brings together technologies, manufacturers, scientists, and clinicians to achieve definitive correction for our EB patients.”
If the platform succeeds in EB, the researchers believe a similar strategy could eventually be adapted for other inherited skin conditions, more than 1,000 of which currently lack a curative treatment.
Building a system that can be reused
Collectively, rare diseases affect millions of people, and approximately 95% have no cure. Individually, however, each condition may affect too few patients to support the conventional commercial model for developing a drug.
THRIVE is betting that much of that work can be shared.
The gene editor, delivery vehicle, manufacturing process, and trial structure could function as a common platform. For a new disease, researchers might swap out the genetic instructions guiding the treatment while leaving much of the surrounding system intact, more like changing one component in a well-tested machine than constructing a new machine each time.
Within three years, ARPA-H expects participating teams to begin first-in-human studies in which a single umbrella trial can evaluate several treatments for several related diseases. By year five, the agency expects the teams to add more therapies and conditions to those shared clinical and regulatory structures.
There are no guarantees. Editing DNA inside the human body must meet an exceptionally high safety bar, and personalized treatments still pose difficult questions about manufacturing, cost, access, and long-term monitoring.
But for families affected by rare diseases, the status quo carries its own cost. A scientifically possible treatment offers little comfort if it cannot be developed before a child becomes critically ill, or if the process is so expensive that it can never reach most patients.
Though focusing on two very different pathways, both Stanford teams are working toward the same destination: a system in which the rarity of a child’s disease no longer determines whether developing a treatment is possible.
