**6. Rescue and Therapeutic Solutions**

In recent years, basic science has elucidated the molecular etiology underlying PXE [6,8,13,76,87,96,124,125], which has led to rapid advances in the development of many potential therapeutic options for PXE and GACI and the recent completion of three pilot clinical trials [18–20,80,99,117,126–130]. Among the several approaches (summarized in Table 1) that have been considered are enzyme replacement therapy, rescue drugs, and enzyme inhibitors, as well as exogenous compounds such as PPi. All target various steps in the ABCC6 pathway (Figure 3) with the goal of either slowing or reversing the progression of the disease. Figure 3 outlines many of these approaches and indicates the targeted parts of the molecular pathway. We discern two main categories of therapeutic solutions that have undergone development and testing, thus far. Most of these therapeutic

solutions have been tested in pre-clinical animal models (mice and zebrafish) and a few phase I/II clinical trials. Beyond what is described in these paragraphs, note that there are larger scale trials in preparation and further drug development that are taking place based on past lessons and data. We cannot describe these ongoing efforts here for reasons of confidentiality or simply for lack of detailed information.


**Table 1.** Preclinical studies and early clinical trials for PXE (and GACI).

\* Denotes treatments undergoing clinical trials, † currently in use in PXE patients. PXE, pseudoxanthoma elasticum; GACI, generalized arterial calcification of infancy; MGP, matrix gla protein; PPi, pyrophosphate.

**Figure 3.** Tested therapeutic Interventions targeting different steps in the ABCC6 pathway to prevent calcification in PXE/GACI. Red boxes point to approaches that were tested in preclinical models and that are currently under human evaluation/trials.

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