New data on Cytonet’s investigational liver cell therapy (LCT) found it may help temporarily stabilise paediatric patients with Urea Cycle Disorders (UCD) while they await liver transplantation. The study was presented recently at the 2014 Joint Garrod and Canadian Newborn and Child Screening Symposium in Ottawa, Ontario, Canada.
UCD comprise a group of rare, potentially life-threatening disorders of liver metabolism that affect newborns and infants. In its severe form it causes ammonia to accumulate in the body, leading to irreversible damage of the nervous system including the brain.
For patients suffering from severe neonatal UCD, liver transplantation remains the only option for long-term stabilisation. However, liver transplantation is still very difficult in small infants and success rates clearly increase in older infants.
Liver cell therapy may help keep the patient stable until a liver transplant is possible. It involves collecting healthy cells from donated livers not suitable for organ transplantation. These cells are infused into the portal vein in six sessions on six consecutive days. Cytonet currently has two ongoing multicentre clinical trials in US and Canada (SELICA III), and in Germany (SELICA V) exploring the use of liver cell therapy for patients with UCD.
In his presentation, Aneal Khan, MD, lead author and assistant professor of medical genetics and paediatrics at the University of Calgary and Alberta Children’s Hospital in Calgary, Alberta, Canada, shared case reviews of patients participating in the SELICA III trial. Between October 2012 and December 2013, Dr Khan treated four patients under the age of 3 with Cytonet’s liver cell therapy. All four achieved a period of sustained normalisation of ammonia levels within 30 days, though the duration of control varied from patient to patient.
One patient was successfully bridged to solid organ liver transplantation and two are currently stable, awaiting eligibility clearance. One patient died as a result of complications due to the underlying disease prior to organ transplantation.
“After receiving liver cell therapy, all four of our patients showed normal and stable ammonia levels for a period of time – some patients went up to 10-12 months without a single hyperammonemic episode. In patients where a suitable donor organ was found, liver cell therapy was a successful bridge to liver transplant that also helped the patient receive adequate nutrition to support growth and development,” said Dr. Khan.
“The much longer survival of boys with a deletion in the OTC gene after liver cell therapy shows that this approach shows promise in changing the natural history of a disease that has been universally fatal in our population up until now.”
In December 2013, Cytonet submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) seeking approval for its liver cell therapy for the treatment of Urea Cycle Disorders in children.
According to the National Urea Cycle Disorders Foundation (NUCDF), urea cycle disorders comprise a group of genetic disorders leading to a deficiency of one of the six enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. These include carbamoyl phosphate synthetase I (CPS I) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase (ASS) deficiency (which is also known as citrullinemia), argininosuccinate lyase (ASL) deficiency and arginase 1 deficiency (hyperargininemia).
The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is removed from the blood and converted to urea. Normally, the urea is transferred into the urine and removed from the body. In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic substance, and is not removed from the body resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it causes irreversible brain damage, coma and/or death.
Urea cycle disorders are included in the category of inborn errors of metabolism. Inborn errors of metabolism represent a substantial cause of brain damage and death among newborns and infants. Because many cases of urea cycle disorders remain undiagnosed and/or infants born with the disorders die without a definitive diagnosis, the exact incidence of these cases is unknown and underestimated. It is believed that up to 20 percent of Sudden Infant Death Syndrome cases may be attributed to an undiagnosed inborn error of metabolism such a urea cycle disorder.
