Reversing disrupted developmental sterol biosynthesis by prescription medications

Compound heterozygous mutations of the DHCR7 gene give rise to a developmental disorder known as Smith- Lemli-Opitz syndrome (SLOS). The loss of DHCR7 function in these patients disrupts the cholesterol biosynthesis pathways, resulting in two hallmarks of the disorder: abnormally low cholesterol/desmosterol

levels and high concentrations of the immediate precursor 7-DHC. 7-DHC is the most reactive lipid known to date, and 7-DHC derived oxysterols are toxic for both neurons and glia. The few current treatments for SLOS are symptomatic, and largely inefficient. We are focusing on finding a SLOS treatment by which 7-DHC levels

can be reduced and toxicity can be counteracted while conserving residual cholesterol biosynthesis. Our high throughput screening of 727 compounds with a history of use in human clinical trials revealed that 40 of these compounds decreased 7-DHC formation in Dhcr7-deficient N2a cells. Following up on initial findings in vitro

and in vivo we found that three compounds were particularly effective in reducing toxic 7-DHC levels – ziprasidone (ZIP), valproic acid (VPA) and hydroxyzine (HYZ) – both in human dermal fibroblasts of SLOS patients and in SLOS mouse models. These three compounds act at different sites of post-lanosterol

biosynthesis. Our central hypothesis is that postnatal treatment with ZIP, VPA and/or HYZ will improve SLOS sterol profile, improving the neurochemical disruptions seen in a SLOS transgenic mouse model, and establishing a rational basis for the therapeutic use of one of these medications in SLOS patients. We also

propose that the beneficial effects of ZIP, VPA and/or HYZ will be summative or synergistic when combined with a Vitamin E (VIT-E) rich diet. Finally, in an exploratory high-throughput screening we will attempt to identify additional, natural compounds that could also counteract the rise and effects of 7-DHC without

suppressing residual sterol biosynthesis. We anticipate that the biological findings we obtain will provide a framework for follow-up clinical trials on SLOS patients. Furthermore, these medications could also be beneficial for treatment of other inborn errors of sterol metabolism.