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Correction of a Traffic-Defective Missense ABCB11 Variant Responsible for Progressive Familial Intrahepatic
Martine Lapalus1, Elodie Mareux1, Rachida Amzal1
1Université Paris-Saclay, Inserm, Physiopathogénèse et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France.
International Journal of Molecular Sciences
|June 13, 2025
Summary
New drugs show promise in correcting bile salt transporter defects in Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2). These compounds improve the trafficking and function of the defective ATP-binding cassette B11 (ABCB11) protein, offering potential new treatments for PFIC2 patients.
Area of Science:
- Hepatology and Genetic Liver Diseases
- Molecular Pharmacology and Drug Discovery
- Membrane Transport Proteins
Background:
- Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2) is a severe liver disorder caused by mutations in the ABCB11 gene, which encodes the bile salt export pump (BSEP).
- Some missense mutations lead to mis-trafficking of the BSEP protein to the canalicular membrane, impairing bile salt excretion.
- 4-phenylbutyrate (4-PB) has demonstrated in vitro efficacy in partially correcting mis-trafficked BSEP variants and improving patient outcomes.
Purpose of the Study:
- To evaluate the ability of 4-phenylbutyrate (4-PB) analogs, homologous drugs, and novel chemical compounds to rescue the canalicular expression and activity of a folding-defective Abcb11 variant (Abcb11R1128C).
- To identify new pharmacological agents that can correct the trafficking and function of misfolded BSEP protein in PFIC2.
Main Methods:
- Screening of a chemical library and design of novel compounds based on structural homology to 4-PB.
- In vitro evaluation in hepatocellular polarized cell lines to assess canalicular localization of Abcb11R1128C after transfection.
- Assessment of 3H-taurocholate transport restoration in Madin-Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and Ntcp/Slc10A1.
Main Results:
- Several compounds, including glycerol phenylbutyrate (GPB), phenylacetate (PA), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB), and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC), significantly increased canalicular Abcb11R1128C protein levels.
- GPB, PA, ursodeoxycholic acid (UDCA), and other tested agents (SAHA, C18, VX-445, VX-661), alone or in combination, effectively corrected both the trafficking and transport activity of the Abcb11R1128C variant.
- These findings highlight the potential of specific chemical compounds to restore BSEP function in vitro.
Conclusions:
- Novel chemical correctors, including 4-PB derivatives and other agents, can effectively rescue the canalicular expression and bile salt transport activity of the folding-defective Abcb11R1128C variant.
- These identified compounds represent promising therapeutic candidates for developing new pharmacological strategies for PFIC2 patients with ABCB11 missense variations.
- Further investigation into these correctors may lead to improved treatment options for individuals with ABCB11 deficiency.
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