From the Cover: Inhibitors of Nicotinamide Phosphoribosyltransferase Cause Retinal Damage in Larval Zebrafish

Area of Science:

• Biochemistry
• Toxicology
• Oncology

Background:

• Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in cellular energy metabolism and a target for cancer therapy.
• Small molecule NAMPT inhibitors show therapeutic promise but face challenges due to preclinical retinal toxicity.
• Current preclinical models for assessing ocular toxicity are often slow and resource-intensive.

Purpose of the Study:

• To evaluate larval zebrafish as a model for predicting retinal toxicity associated with NAMPT inhibitors.
• To assess the utility of zebrafish for high-throughput screening of drug candidates targeting NAMPT.
• To establish a correlation between zebrafish visual toxicity and in vitro potency against human tumor cells.

Main Methods:

• Larval zebrafish were exposed to various NAMPT inhibitors.
• Behavioral assays were used to assess visual versus auditory response.
• Histopathological analysis was performed to confirm retinal damage.
• Zebrafish toxicity data were correlated with in vitro drug potencies.

Main Results:

• NAMPT inhibitor treatment in zebrafish resulted in a loss of response to visual cues.
• Histopathology confirmed retinal damage in treated zebrafish.
• A positive correlation was observed between the impact on zebrafish vision and in vitro potency against human tumor cells.
• Zebrafish toxicity mirrored on-target effects of NAMPT inhibition.

Conclusions:

• Larval zebrafish serve as an effective model for predicting NAMPT inhibitor-associated retinal toxicity.
• Zebrafish offer a high-throughput, cost-effective alternative to mammalian systems for ocular toxicity screening.
• This model facilitates the identification of safer drug candidates and accelerates oncology drug development.