Hydroxyzine Effects on Post-Lanosterol Biosynthesis in Smith-Lemli-Opitz Syndrome (SLOS) Models

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Smith-Lemli-Opitz syndrome (SLOS) is a rare developmental disorder caused by pathogenic variants in the 7-dehydrocholesterol reductase (DHCR7) enzyme.
• This enzyme deficiency leads to the accumulation of 7-dehydrocholesterol (7-DHC), which oxidizes into cytotoxic oxysterols, contributing to disease pathology.

Purpose of the Study:

• To investigate the potential of hydroxyzine (HYZ), identified via high-throughput screening, to mitigate 7-DHC accumulation in SLOS.
• To assess the biochemical effects of HYZ on post-lanosterol biosynthesis in various SLOS models.

Main Methods:

• Utilized Dhcr7-deficient Neuro2a cells, neuronal and glial cultures from Dhcr7^T93M/T93M transgenic mice, and human dermal fibroblasts from SLOS patients.
• Employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) for detailed biochemical analyses of sterol intermediates.

Main Results:

• Hydroxyzine demonstrated a modulatory effect on post-lanosterol biosynthesis across all tested SLOS models.
• Observed significant reductions in 7-DHC and other intermediates in specific models, but also complex, dose-dependent, and variable changes in multiple sterol analytes.
• Human fibroblasts showed decreased 7-DHC, 7-dehydrodesmosterol (7-DHD), and dihydrolanosterol (DHL) with concurrent increases in zymosterol (ZYM), zymostenol (ZYME), and 8-dehydrocholesterol (8-DHC).

Conclusions:

• Hydroxyzine impacts sterol biosynthesis in SLOS models, reducing key pathogenic intermediates like 7-DHC.
• The complex and variable biochemical responses necessitate further investigation to ascertain the net therapeutic benefit of HYZ in SLOS.
• Future research should evaluate whether the observed reductions in detrimental sterols are offset by increases in other potentially harmful intermediates.