A Novel High-Content Screening Assay Identified Belinostat as Protective in a FSGS-Like Zebrafish Model

Area of Science:

• Nephrology
• Drug Discovery
• Zebrafish Models

Background:

• Focal Segmental Glomerulosclerosis (FSGS) damages podocytes, leading to kidney scarring and filtration loss.
• Current FSGS therapies are limited, with no specific drugs targeting podocytes.
• Drug repurposing offers a strategy to find new treatments for FSGS.

Purpose of the Study:

• To develop and implement a high-content screening (HCS) assay in zebrafish to identify drugs that protect podocytes.
• To screen a library of compounds, including FDA-approved drugs, for efficacy against FSGS-like pathology.
• To validate promising drug candidates for potential translation to human FSGS treatment.

Main Methods:

• Established a novel zebrafish strain expressing fluorescent markers in podocytes for monitoring cell health and proteinuria.
• Induced FSGS-like lesions in zebrafish using metronidazole exposure.
• Conducted an in vivo HCS assay screening 138 drugs and compounds for podocyte-protective effects.

Main Results:

• Successfully developed and validated a novel in vivo HCS assay for FSGS drug discovery.
• Identified seven protective drugs/compounds from the screened library.
• Confirmed that the FDA-approved drug belinostat demonstrated significant protective effects against larval FSGS.

Conclusions:

• The developed zebrafish HCS assay is a powerful tool for identifying FSGS therapeutics.
• Belinostat and other pan-histone deacetylase inhibitors show significant potential for treating FSGS.
• These findings pave the way for further investigation and clinical translation of novel FSGS treatments.