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Toxicol Sci. 2015 Mar;144(1):163-72. doi: 10.1093/toxsci/kfu268. Epub 2014 Dec 11.

Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase.

Author information

1
*Safety Assessment, Genentech, South San Francisco, California 94080, DMPK, Genentech, South San Francisco, California 94080, In-Vivo Pharmacology, Genentech, South San Francisco, California 94080, Translational Oncology, Genentech, South San Francisco, California 94080, Discovery Chemistry, Genentech, South San Francisco, California 94080 misner.dinah@gene.com.
2
*Safety Assessment, Genentech, South San Francisco, California 94080, DMPK, Genentech, South San Francisco, California 94080, In-Vivo Pharmacology, Genentech, South San Francisco, California 94080, Translational Oncology, Genentech, South San Francisco, California 94080, Discovery Chemistry, Genentech, South San Francisco, California 94080.

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone. NAMPT is of interest for oncology, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), which is considered a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. This manuscript describes NAMPT inhibitor-induced retinal toxicity that was identified in rodent safety studies. This toxicity had a rapid onset and progression and initially targeted the photoreceptor and outer nuclear layers. Using in vivo safety and efficacy rodent studies, human and mouse cell line potency data, human and rat retinal pigmented epithelial cell in vitro systems, and rat mRNA expression data of NAMPT, nicotinic acid phosphoribosyltransferase, and nicotinamide mononucleotide adenylyltransferease (NMNAT) in several tissues from rat including retina, we demonstrate that the retinal toxicity is on-target and likely human relevant. We demonstrate that this toxicity is not mitigated by coadministration of nicotinic acid (NA), which can enable NAD production through the NAMPT-independent pathway. Further, modifying the physiochemical properties of NAMPT inhibitors could not sufficiently reduce retinal exposure. Our work highlights opportunities to leverage appropriately designed efficacy studies to identify known and measurable safety findings to screen compounds more rapidly and reduce animal use. It also demonstrates that in vitro systems with the appropriate cell composition and relevant biology and toxicity endpoints can provide tools to investigate mechanism of toxicity and the human translation of nonclinical safety concerns.

KEYWORDS:

eye; messenger RNA; nicotinamide adenine dinucleotide; nicotinic acid mononucleotide; pathology; retinal degeneration; retinal pigmented epithelial cell culture; tumor metabolism

PMID:
25505128
DOI:
10.1093/toxsci/kfu268
[Indexed for MEDLINE]

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