Audentes is developing AT342 for the treatment of Crigler-Najjar Syndrome
Crigler-Najjar Syndrome (CN) is a rare, congenital autosomal recessive monogenic disease characterized by severely high levels of bilirubin in the blood and risk of irreversible neurological damage and death. Life expectancy is 30 years of age. CN is estimated to affect approximately one in 1,000,000 newborns. Infants with CN develop severe jaundice shortly after birth resulting in rapid presentation and diagnosis. CN is caused by mutations in the gene encoding the UGT1A1 (uridine-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1) enzyme resulting in an inability to convert unconjugated bilirubin to a water-soluble form that can be excreted from the body. Clinical diagnosis is confirmed via genetic testing of the UGT1A1 gene. The current standard of care for Crigler-Najjar Syndrome is aggressive phototherapy for more than ten to 12 hours per day using intense LED or fluorescent light focused on the bare skin, while the eyes are shielded. Phototherapy speeds bilirubin decomposition and excretion, lowering serum bilirubin levels. Phototherapy wanes in effectiveness beginning around age four due to thickening of the skin and a reduction in surface area to body mass ratio, and a liver transplant may be required for survival.
We are developing AT342, an AAV vector containing a functional version of the UGT1A1 gene. Preclinical data in murine models of the disease demonstrate AAV-UGT1A1 significantly reduces bilirubin levels, even at UGT1A1 liver expression levels of just five to eight percent of normal. We are advancing AT342 with the goal of administering a single dose that results in a significant, durable reduction in serum bilirubin, a reduction in or elimination of lengthy daily phototherapy, and elimination of the need for a liver transplant. We believe that serum bilirubin levels will be a clinically relevant endpoint and that determination of efficacy of AT342 will be straightforward due to the ease and reliability of measurement.