**8. Summary and Conclusions**

Despite the relative infrequency of the inherited forms of progressive intrahepatic cholestasis, the symptoms are severe, and about half of the patients progress to a stage of the disease that makes them candidates for liver transplantation. Therefore, the quest for identification of causal therapies that go beyond the purely symptomatic treatment of pruritus is an important objective. Attempts to alleviate disease symptoms by transcriptional upregulation are directed towards missense mutations with preserved functionality. Similarly, those mutants that are folding- and consequently trafficking-deficient have successfully been treated with folding correctors. Recent evidence points to yet another

therapeutic path, in which the function of impaired BSEP mutants is potentiated by drugs that were initially developed to treat different disease entities, which are also associated with a malfunction of human ABC proteins. However, BSEP missense or deletion mutations and mutants with compromised functionality will only be amenable to therapy using gene editing. Current advances in gene editing technologies have not been considered in this review, as they are subject to another article in this Special Issue. The availability of the recently published cryo-EM structure of BSEP can be considered an important basis for structure-based drug design. Moreover, structural data, MD-simulations and site-directed mutagenesis studies continuously expand our understanding of the functional biology of BSEP.

We also briefly summarized available in vitro model systems for the functional characterization of BSEP, animal models and case reports discussing emerging clinical therapies. The perspective that treatment regimens combining small molecules with different mechanisms of action will ultimately lead to an improvement in the quality of life and life span of affected individuals appears promising.

**Author Contributions:** Conceptualization, P.C. and T.S.; writing—original draft preparation, M.I.S., Y.D.-C. and D.S.; writing—review and editing, M.I.S., Y.D.-C., D.S., T.S. and P.C.; visualization, D.S., Y.D.-C., T.S.; project administration, T.S. and P.C.; funding acquisition, P.C. and T.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** Open Access Funding by the Austrian Science Fund (FWF), grant numbers SFB3509 (to P.C.), SFB3524 (to T.S.) and (P32017 to T.S.).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not available.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
