Therapeutic innovations for liver diseases caused by defects in the biliary transporter ABCB4/MDR3 – ABCTher

Rare diseases affect over 30 million Europeans. They usually have a genetic basis and efficient treatments are not available in most cases. Therefore, finding new therapies for patients affected by rare diseases is a major challenge for the scientific and medical communities. ABC (ATP Binding Cassette) transporters form a superfamily of proteins with approximately fifty members in human. Molecular defects in several of these transporters have been identified in patients with hereditary diseases, such as cystic fibrosis (ABCC7), Stargardt disease (ABCA4), adrenoleukodystrophy (ABCD1), Tangier disease (ABCA1), and rare biliary diseases (ABCB4, ABCB11, ABCC2).

This project is dedicated to the study of ABCB4 (ATP Binding Cassette subfamily B member 4), also named MDR3 (MultiDrug Resistance protein 3). ABCB4 is a transmembrane protein, with twelve transmembrane domains and two nucleotide-binding domains (NBDs), exclusively expressed at the canalicular membrane of hepatocytes. Its function is to translocate phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane in an energy-dependent manner. Thereby, phosphatidylcholine can interact and form mixed micelles with bile acids and cholesterol in the aqueous environment of bile, thus preventing the detergent action of free bile acids on biological membranes and the formation of cholesterol gallstones.

Variations of the ABCB4 locus have been found in patients with several rare biliary diseases, i.e. Low Phospholipid-Associated Cholelithiasis (LPAC) syndrome, Intrahepatic Cholestasis of Pregnancy (ICP), Progressive Familial Intrahepatic Cholestasis type 3 (PFIC3) or fibrosing cholestatic diseases. PFIC3 is a rare disease characterized by the early onset of cholestasis that frequently leads to cirrhosis and liver failure before adulthood. The unique proposed therapy for ABCB4-related diseases is the administration of UrsoDeoxyCholic Acid (UDCA), a therapeutic bile acid which partially reverts the symptoms of ABCB4 defects in patients. This therapy is efficient in a majority of patients with ICP or LPAC syndrome but not all, and more than half of PFIC3 patients do not or poorly respond to UDCA. In case of failure of UDCA treatment for these patients, the only alternative is liver transplantation.

The objectives of our project are the following:
1) Identify molecular partners of ABCB4 involved in the traffic and/or activity of this transporter that could be targeted in pathological settings.
2) Determine the molecular defects induced by ABCB4 variations causing the most severe forms of biliary diseases that do not or poorly respond to UDCA therapy. This will allow us to determine which ABCB4 mutants might benefit from a new pharmacotherapy able to restore normal traffic and/or activity of the transporter.
3) Identify new molecules with therapeutic potential in order to treat patients with ABCB4-related diseases who do not or poorly respond to UDCA therapy. These molecules will be sought using candidate and high throughput screening approaches in disease-mimicking cell models, based on their ability to restore ABCB4 defects induced by missense mutations identified in patients.

Ultimately, the development of new targeted therapies will be a promising alternative to liver transplantation for patients with biliary diseases related to molecular defects due to ABCB4 variations, mainly PFIC3. Moreover, therapies that will be newly identified in the frame of this project might also benefit to more diseases caused by variations in other ABC transporters.