A 14-month-old boy has made "incredible" progress after becoming the first patient worldwide to receive a novel gene therapy for a rare metabolic disorder, potentially heralding a new era in treating severe genetic liver diseases.
Tomas, diagnosed with ornithine transcarbamylase (OTC) deficiency as a newborn, received the experimental gene therapy ECUR-506 last summer at Great Ormond Street Hospital (GOSH) in London. Six months after treatment, he no longer requires specialized dietary restrictions or ammonia scavenger medications that are typically lifelong necessities for patients with this condition.
OTC deficiency affects approximately 15 people annually and is characterized by the body's inability to properly process ammonia, a toxic byproduct of protein metabolism. The condition results from a genetic deficiency in a liver protein responsible for ammonia detoxification, allowing dangerous levels to accumulate in the blood.
"Even slightly elevated levels of ammonia in the blood can be toxic," explained Dr. Julien Baruteau, principal investigator for the study and consultant in metabolic medicine at GOSH. "If left untreated, it can cause life-threatening complications including brain damage, coma or seizures."
Revolutionary Gene Therapy Approach
The OTC-HOPE trial is investigating ECUR-506, a gene therapy delivered via infusion to reach the patient's liver cells. Unlike previous gene therapies, ECUR-506 employs a novel precision approach where the functioning OTC gene copy is inserted at a specific location in one of the chromosomes.
"This novel technology may herald new avenues to treat babies with severe liver genetic diseases," said Dr. Baruteau, who is also a clinician scientist fellow at University College London Great Ormond Street Institute of Child Health. "To our knowledge, this is the first time a baby has received a liver-directed gene editing therapy."
The therapy aims to provide comparable results to liver transplantation—currently the standard of care for severe cases—but through a single treatment with potentially fewer complications.
Tomas's Journey
Tomas's symptoms appeared when he was just one week old. His mother Mariana, from Ilford in east London, recalled the frightening experience: "Tomas became unresponsive at home and wouldn't open his eyes, which was really scary."
After an initial hospital visit where doctors struggled to identify the problem, Tomas was transferred to GOSH. There, specialists quickly determined his ammonia levels were dangerously elevated and diagnosed him with OTC deficiency.
The family was offered enrollment in the OTC-HOPE trial as an alternative to liver transplantation, which would have been the traditional treatment approach for his severe case.
"We're extremely grateful for the help and support we've had from the doctors and nurses at GOSH," said Mariana. "We thought a liver transplant would be Tomas's only option and this would be tricky. We're so pleased he was able to have the gene therapy—it's been incredible."
Promising Clinical Outcomes
The results thus far have exceeded expectations. "He no longer needs the standard treatment of ammonia scavengers and is eating age-appropriate levels of protein for a baby of his age," Dr. Baruteau reported.
This outcome is particularly significant given the limitations of conventional treatments. Standard approaches for OTC deficiency include protein restriction and medications known as "scavenger therapy" to help remove ammonia from the blood. However, these interventions often prove insufficient for severe cases, especially in male infants like Tomas, who typically require liver transplantation—a procedure with significant risks.
Dr. Baruteau expressed optimism about the therapy's potential: "I'm hopeful that Tomas will continue along this encouraging trajectory and that other babies who enroll in this study will have similar experiences."
Future Implications
The successful treatment of Tomas represents a potential paradigm shift in managing not only OTC deficiency but possibly other severe genetic liver disorders as well. The precision gene editing approach could eliminate the need for liver transplantation in infants with these conditions, avoiding the associated risks and lifelong immunosuppression.
Dr. Baruteau is presenting initial data from this groundbreaking case at the Annual Clinical Genetics Meeting in Los Angeles, where it is expected to generate significant interest among researchers and clinicians specializing in genetic disorders.
As the OTC-HOPE trial continues to enroll patients, the medical community will be watching closely to see if Tomas's remarkable response can be replicated, potentially establishing a new standard of care for babies born with this rare but devastating condition.
