*7.3. Chemical Correction with 4-PB*

A large number of mutations have been reported to interfere with either BSEP folding or its correct trafficking to the canalicular membrane. Among these are the E297G and D482G mutations, which account for approximately 60% of PFIC2 cases in the European population [119]. The underlying hypothesis behind the concept of chemical correction is that these mutants, when rescued to the canalicular membrane, would function normally, and thus the disease phenotype would be alleviated. Furthermore, 4-PB, an FDA-approved drug for the treatment of urea cycle disorders, functions as a chemical chaperone for folding-deficient BSEP variants [56]. Indeed, in vitro studies in HEK293 and MDCKII cell lines indicated that upon treatment with 4-PB, these mutants would show enhanced surface expression, as well as increased TCA transport activity [103,104]. Furthermore, in support

of the validity of this concept, 4-PB treatment also increased the biliary excretion of TCA in animal models [104].

Recently, use of 4-PB showed promising results in a clinical setting. Gonzales and co-workers [97,98] showed that treating PFIC2 patients carrying at least one mutation (out of p.G982R, p.R1128C and p.T1210P) with 4-PB led to an improvement in serum liver parameters, including the serum bile acid concentration, and a reduction in the pruritus score. Similarly, a preterm infant diagnosed with BSEP-related cholestasis was treated with 4-PB and showed an improvement of the disease symptoms [134]. In addition, BRIC2 patients have also been treated successfully with 4-PB [109]. The therapeutic doses ranged from 150 to 500 mg/kg/day. In some patients, a 4-PB dose of ≤ 350 mg/kg/day had no beneficial effect, while a high dose regimen (500 mg/kg/day) improved disease symptoms [109,117]. In a recent study, two PFIC II patients were given a combination of 4-PB, oxcarbazepine (a peripheral nerve stabilizer reducing pruritus) and maralixibat (an apical sodium-dependent bile acid transporter inhibitor), which had a beneficial effect on disease markers [101]. Most of these studies did not show apparent side effects, even in the high-dose regimen. However, psychological disorders (bipolar and related disorders) have been connected to the use of 4-PB in a clinical setting [135].
