# Reversing disrupted developmental sterol biosynthesis by prescription medications

> **NIH NIH R56** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $230,250

## Abstract

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.

## Key facts

- **NIH application ID:** 11137179
- **Project number:** 1R56HD111119-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** ZELJKA KORADE
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $230,250
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11137179

## Citation

> US National Institutes of Health, RePORTER application 11137179, Reversing disrupted developmental sterol biosynthesis by prescription medications (1R56HD111119-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11137179. Licensed CC0.

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