PFIC2 is a rare disorder caused by mutations in ABCB11 gene encoding for BSEP protein, responsible for the transport of bile salts (BS) from hepatocytes to the canalicular lumen. BSEP mutations result in impaired BS secretion from hepatocytes leading to severe liver damage. Currently, liver transplantation is the only curative option. AAV-based gene therapy targeting the liver could represent a safe and efficient option for PFIC2 patients by restoring long-term hepatic BSEP expression and physiological bile secretion. 

We generated and characterized an Abcb11-/- mouse model of PFIC2 in a C57BL/6 background. PFIC2 disease parameters were impaired in both sexes with females presenting a more severe phenotype and recapitulating the human disease more closely than males. We assessed the therapeutic efficacy of gene therapy in PFIC2 mice using a liver-tropic AAV8 vector carrying a codon-optimized human BSEP cDNA under the control of a liver-specific promoter (VTX-802(8)). PFIC2 females treated with VTX-802(8) at 5 weeks of age showed normalization of serum biomarkers levels at three weeks post-injection. Moreover, these mice showed a partial but significant reversion of hepatomegaly, and the release of BS from the liver to bile and small intestine was significantly increased four months post-injection.

These early results indicate that VTX-802(8) has therapeutic potential for PFIC2. However, further development of the AAV vector and/or combination with other pharmacological products, might be investigated. The development of a durable cure for PFIC2 and its translation to the clinic would provide a life-changing alternative for these pediatric patients with high unmet medical need.