Crigler-Najjar syndrome type 1 (CN1) is an an autosomal recessive disease caused by a marked decrease in uridine-diphosphateglucuronosyltransferase (UGT1A1) enzyme activity. Delivery of a modified messenger RNA encoding for UGT1A1 (hUGT1A1-modRNA) as a lipid nanoparticle (LNP) is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in CN1 patients. In vivo mechanism of action and clinical pharmacology is unknown.
- Preclinical: This model helped guide the selection of preclinical candidates, accelerate the termination of a program based on predicted low therapeutic window, reduced the number of in vivo studies, and provided insight into the mechanism of action of mRNA LNP.
- Clinical: This model helped inform recommended safe starting dose, impacted clinical strategy in term of patient populations for Ph1, and helped project consequences of nonlinear parameters that do not follow typical allometric scaling rules to inform first-in-human dose.