News release

From: Children's Medical Research Institute (CMRI)

Gene editing advance shows promise for rare liver disease

Researchers have taken an important step toward solving one of the biggest challenges in gene therapy for children with metabolic liver disorders: growth itself. As a child's liver grows, some gene therapies that once worked can gradually lose their effect, since the treated cells are eventually outnumbered by new, untreated ones.

The team at Children's Medical Research Institute (CMRI), led by Associate Professor Samantha Ginn, has developed a genome editing approach that repairs a faulty gene directly at its natural location in the liver, rather than adding an extra copy of it. The research, published in Molecular Therapy, focused on ornithine transcarbamylase (OTC) deficiency, a severe genetic liver disorder that prevents the body from properly breaking down waste products from protein digestion.

"We showed that genome editing could efficiently repair the OTC gene in patient-derived human liver cells and in laboratory models of the disease, restoring its function while preserving the liver's normal pattern of OTC expression," says Associate Professor Ginn. "This also corrected the underlying metabolic problem. This matters because the approach is designed to correct most OTC mutations and could provide a more durable treatment than conventional gene replacement, particularly in growing children."

More than 500 different gene mutations can cause OTC deficiency. Treating each mutation individually would be enormously impractical, so scientists looked for approaches that work regardless of which specific mutation a patient carries.

Conventional gene therapy for OTC deficiency works by delivering a working copy of the gene into liver cells, allowing the liver to function normally. But because this extra gene copy exists separately from a person's own DNA, it can be diluted or lost over time as a child's liver grows and cells divide, a particular problem for very young patients who still have years of growth ahead of them.

"This is an important advance because we achieved high levels of functional, targeted repair at the native OTC locus in human liver cells, using a mutation-agnostic strategy," Associate Professor Ginn explains. "Unlike conventional gene therapy, which introduces an extra copy of the gene, this approach places the therapeutic sequence under the control of the gene's own regulatory machinery and restored its normal metabolic zonation across the liver."

The method, known as homology-independent targeted integration (HITI), uses two viral delivery vehicles working together: one carries the gene editing tools and the other carries the corrective DNA, which has no built in "on switch" of its own because it captures the gene's natural one. In laboratory models of OTC deficiency, urinary orotic acid concentrations, a key marker of urea cycle function, normalised within three weeks of treatment, and by the study's endpoint, blood ammonia concentrations showed no significant difference from healthy control levels even after a protein challenge designed to stress the system. OTC activity was detected in up to 40% of liver cells, and whole-liver OTC activity more than doubled compared to untreated models.

The team then tested the approach in patient-derived human liver cells transplanted into specially engineered models, and found it achieved high levels of functional, targeted repair, restoring OTC expression in up to 48% of human cells. One of the most important features of this approach is that it is designed to work regardless of which specific mutation is causing a person's OTC deficiency, offering the potential to help far more patients without needing a treatment tailored to each individual genetic variation.

Interestingly, the research also turned up an unexpected result. "The most surprising finding was that, although the therapeutic DNA reached the intended location and restored gene function at high efficiency, it was incorporated in more complex arrangements than we had predicted," says Associate Professor Ginn. "Understanding these previously underappreciated outcomes gives us important insights for improving the precision of genome editing therapies moving forward."

This research fits into a much larger conversation happening in genetic medicine right now. "It speaks directly to the challenge of making gene therapy durable in young children, whose growing livers can lose conventional non-integrating gene therapies over time," Associate Professor Ginn says.

"It also contributes to broader discussion about moving genome editing beyond treatments tailored to individual mutations towards scalable approaches that could benefit larger groups of patients with rare genetic diseases."