Wednesday, December 4, 2024
12/4/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
