First patient treated with groundbreaking gene therapy trial

14-month-old Tomas was diagnosed with the rare condition ornithine transcarbamylase (OTC) deficiency when he was a few weeks old.

OTC deficiency is a serious genetic disease where ammonia, a waste product that is generated when the body breaks down proteins, builds up in the blood. Ammonia is toxic, especially to the brain, when it accumulates at high levels. Around 15 patients in the UK are diagnosed with the rare condition each year.

Symptoms of the condition first start to show shortly after birth including lethargy, inability to feed, and vomiting. If left untreated, it can cause life threatening complications including seizures, coma and brain damage.

The condition is caused by a genetic defect in the liver enzyme responsible for detoxifying ammonia, so it allows ammonia to build up in the blood. It’s also more severe in baby boys, as the OTC gene is found in the X chromosome. Boys will have a more severe form of the disease if the gene is faulty, as they only have one X chromosome.

Standard treatment for the rare condition is regular medication, known as scavenger therapy, and restricting protein in the diet to control ammonia levels. This stabilises the patient but does not prevent the risk of their condition worsening due to high ammonia levels. In severe cases like OTC deficient baby boys, these hyperammonaemic episodes are common. Therefore, patients may require a liver transplantation to preserve their brain from ammonia damage long-term.

Tomas was a healthy baby when he was born, but when he was just one week old, he started not eating and vomiting.

Mum Mariana, originally from Ukraine but now living in Ilford, said: “Tomas became unresponsive at home and wouldn’t open his eyes which was really scary. We called an ambulance, and we were taken to our local hospital. When we first arrived, the doctors couldn’t determine what was wrong with Tomas. We spent the whole day there, from morning until evening, while they suspected an infection but were not certain. Tomas was getting worse, and unfortunately, the hospital couldn’t help us. That’s when we were transferred by ambulance to GOSH.

“When we arrived at GOSH, within an hour or two, they told us that Tomas’ ammonia level was too high – it was 840. At that moment, I didn’t yet understand what that meant.”

Tomas was diagnosed with OTC deficiency at GOSH and took part in the OTC-HOPE clinical trial. He received the investigational gene therapy, ECUR-506, last summer, in the dedicated NIHR GOSH Clinical Research Facility.

The one-time treatment is delivered via intravenous infusion to reach the patient’s liver cells. The gene editing therapy is designed to permanently restore the damaged OTC gene with a functioning copy.

The novelty of this technology represents a completely new way of inserting a gene. The functioning OTC gene copy is designed to be inserted very precisely at a specified location in one of the chromosomes. Previous approaches did not enable gene integration in chromosomes, leading to loss of efficacy in young children when the liver grows particularly fast. This new approach aims to treat babies and young children with a similar efficacy of a liver transplantation but with a one-time infusion of gene therapy instead.

Mum Mariana continued: “The treatment went well but Tomas didn’t accept it straight away. Tomas needed to have steroid therapy to help alleviate inflammation in his liver, an immune reaction caused by the gene therapy. Six months later and he no longer needs the steroids and is making good progress - he no longer needs a special diet and scavenger medications.

“We’re extremely grateful for the help and support we’ve had from the doctors and nurses at GOSH. We thought a liver transplant would be Tomas’ only option and this would be tricky. We’re so pleased he was able to have the gene therapy - it’s been incredible. We recently celebrated his first birthday!”

Julien Baruteau, consultant in metabolic medicine at GOSH, clinician scientist fellow at University College London Great Ormond Street Institute of Child Health, and principal investigator for the study, said: “We’re pleased to see Tomas’ progress since having the gene therapy. He no longer needs the standard treatment of ammonia scavengers and is eating age-appropriate levels of protein for a baby of his age.

“Standard of care for babies with neonatal OTC deficiency relies on liver transplantation in infancy, a procedure with significant risk of complications. This novel gene therapy approach might enable babies with the condition to avoid this. I’m hopeful that Tomas will continue along this encouraging trajectory and that other babies who enrol in this study will have similar experiences. To our knowledge this is the first time a baby has received a liver-directed gene editing therapy. This novel technology may herald new avenues to treat babies with severe liver genetic diseases.”

For over 20 years, GOSH has been at the forefront of pioneering gene therapies for babies, children, and young people.