Ammonia: A Dangerous Waste Product
Ammonia is a natural byproduct of protein metabolism that must be efficiently removed from the body to prevent toxicity. When ammonia removal is disrupted, ammonia accumulates to dangerous levels in the blood, leading to hyperammonemia. Elevated ammonia levels can cause severe neurological symptoms, including confusion, seizures, coma, and potentially death, making effective ammonia management critical for patient survival and quality of life.
Two conditions where ammonia toxicity drives significant disease burden are urea cycle disorders and hepatic encephalopathy.
Urea Cycle Disorders
Urea cycle disorders (UCDs) are inherited genetic conditions that affect the body’s ability to remove toxic ammonia from the blood. The urea cycle operates in the liver and converts ammonia into urea, which can be safely eliminated. When one of the enzymes or transporters in this pathway is deficient or missing, ammonia accumulates to dangerous levels. There are as many as ~6,500 patients in the U.S. living with UCD today and approximately ~8,000 patients in the EU.
Many UCD patients require strict low-protein diets in combination with nitrogen scavengers. These medications can cause unpleasant side effects, including poor palatability, body odor, and gastrointestinal issues. Some formulations require dosing as many as 40 tablets per day, creating a significant treatment burden. Despite these challenges, strict adherence to these regimens is necessary to reduce the risk of hyperammonemic crises (HACs), a persistent and dangerous threat that can result in severe and permanent neurological symptoms, coma, and death.
Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver disease characterized by cognitive dysfunction and altered consciousness. HE is primarily caused by the body’s inability to detoxify ammonia. This leads to ammonia accumulating in the bloodstream and crossing the blood-brain barrier, causing brain dysfunction that ranges from subtle cognitive impairment to severe confusion and coma, significantly impacting patients' quality of life. Medical records indicate that over 300,000 patients are treated for HE in the U.S. Current treatments focus on reducing ammonia production and promoting its excretion via the gut. However, these regimens are often poorly tolerated, have little to no impact on blood ammonia levels, and many patients suffer from recurrent episodes.
Our Ammonia Lowering Approach: KRRO-121
KRRO-121 is a GalNAc-conjugated oligonucleotide designed to edit RNA in the liver to create a de novo protein variant that increases ammonia clearance capacity. Our preclinical data suggests that KRRO-121 has the potential to be a pan-UCD treatment capable of controlling ammonia levels, enabling diet liberalization and scavenger withdrawal while reducing the frequency of HACs. For HE patients, enhanced ammonia control also has the potential to reduce the risk of recurrent HE episodes. KRRO-121 may offer infrequent subcutaneous dosing, a significant improvement in patient convenience over currently available treatment options that require multiple daily doses. KRRO-121 has the potential to be a differentiated, disease-modifying therapy for both UCD and HE, addressing the fundamental challenge of hyperammonemia.