Hyperammonemia, a metabolic condition, is characterised by abnormally high-levels of ammonia in the blood and can lead to brain injury/death.
Since ammonia is primarily cleared by the liver, liver conditions, such as liver disease, cirrhosis of the liver, or acute liver failure, are the primary cause of hyperammonemia. Urea Cycle Disorders (UCDs) are another major cause of hyperammonemia. UCDs are caused by genetic defects that cause one of the enzymes of the urea cycle to be deficient. Newborns who have a complete deficiency in one of these enzymes typically develop hyperammonemia within hours of birth. For individuals with UCDs the 11-year survival rate for early-onset hyperammonemia has been reported to be 35%.
Treatment of acute hyperammonemia aims at reducing the level of ammonia in the blood and treating complications such as cerebral edema (swelling of the brain). In UCD patients, nitrogen intake needs to be severely restricted and this means that patients are put on an extremely low protein diet (since protein is the major source of nitrogen intake), however this is not recommended for patients with liver disease. Some drugs are available to help lower systemic ammonia but these are short-lived, tend to be given intravenously and are used to treat episodes of severe hyperammonemia. There is a significant need for new treatments that can maintain ammonia levels at, or below, the normal levels in these patients.
Hyperoxaluria, is a metabolic condition characterised by excessive oxalate in the blood and urine.
Oxalate is cleared through the kidneys and excess oxalate causes severe kidney stones and kidney damage. Hyperoxaluria can be classified into two main types: primary hyperoxaluria, a rare genetic disorder caused by mutations in specific genes involved in oxalate metabolism, and secondary hyperoxaluria, which results from external factors such as high dietary oxalate intake, gastrointestinal disorders, or impaired intestinal absorption
Clinically, hyperoxaluria manifests as recurrent kidney stones, hematuria (blood in urine), and pain in the lower back or abdomen. Left untreated, it can progress to chronic kidney disease and end-stage renal failure, necessitating dialysis or kidney transplantation. Early diagnosis is crucial to prevent irreversible kidney damage.
Current treatment strategies for hyperoxaluria include lifestyle changes, such as reduced dietary oxalate intake and increased fluid consumption, to help prevent the formation of kidney stones. Pharmacological interventions can also be employed to reduce stone formation. For primary hyperoxaluria, enzyme replacement therapy, liver transplantation, or a combined liver-kidney transplantation may be necessary in severe cases.
A treatment that could be given several times a year which would ensure low levels of oxalate would therefore be highly beneficial to these patients.