Repurposing the HMG-CoA Reductase Inhibitor Atorvastatin for SRD5A3-CDG.

Area of Science:

• Biochemistry
• Genetics
• Developmental Biology

Background:

• SRD5A3-CDG is a rare genetic disorder affecting N-glycosylation due to SRD5A3 gene mutations.
• Current treatments are limited to symptom management, necessitating novel therapeutic strategies.
• Existing disease models lack suitability for high-throughput drug screening.

Purpose of the Study:

• To develop a C. elegans model for SRD5A3-CDG.
• To identify potential drug candidates for SRD5A3-CDG through drug repurposing.
• To evaluate the therapeutic efficacy of identified candidates in preclinical models.

Main Methods:

• Generated a C. elegans model with the SRD5A3 W19X mutation.
• Performed high-throughput motility-based drug screening using the C. elegans model.
• Validated drug efficacy in patient-derived fibroblasts and assessed molecular changes.

Main Results:

• The C. elegans model exhibited developmental delays, neurological dysfunction, and mevalonate pathway alterations.
• Atorvastatin, an HMG-CoA reductase inhibitor, was identified as a promising drug candidate.
• Atorvastatin treatment rescued disease phenotypes in the worm model and normalized polyprenol-to-dolichol ratios in patient fibroblasts.

Conclusions:

• The developed C. elegans model is a valuable tool for SRD5A3-CDG research and drug discovery.
• Atorvastatin demonstrates therapeutic potential for SRD5A3-CDG, offering a novel repurposing strategy.
• Further investigation into atorvastatin's efficacy and safety for SRD5A3-CDG is warranted.