Retinal Toxicity, in vivo and in vitro, Associated with Inhibition of Nicotinamide Phosphoribosyltransferase

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.

Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration

“…In these clinical studies, thrombocytopenia was demonstrated to be the dose-limiting toxicity (30,33). Retinopathy, degeneration and loss of the photoreceptor and outer nuclear layers of the retina, was reportedly associated with FK866/APO866 and CHS 828/GMX-1778 in the rat (30,34). Similar toxicity findings were also reported for other NAMPT inhibitors (35,36).…”

“…First, this molecule only causes retinopathy in the dog, but not in the rat as compared with other NAMPT inhibitors (30,34,35). Second, the retinal toxicity associated with the molecule could be rescued with NA coadministration.…”

“…It is encouraging that thrombocytopenia was significantly reduced in a murine model when FK866 was coadministered with NA (9), thus indicating that NA coadministration could be a viable approach. However, more recent studies reported that NA coadministration failed to rescue the retinal toxicity and also abolished the efficacy of NAMPT inhibitors in tumor xenograft models derived from NAPRT1-deficient cancer cell lines (34)(35)(36). On the basis of these findings, it remained unclear whether NA coadministration could be used to mitigate the toxicities associated with NAMPT inhibition, especially the retinal toxicity.…”

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

“…The relevance of the NAMPT-E2F2-ID pathway to these specific molecular contexts is an interesting question for future investigation. It should be noted, however, that inhibiting NAMPT carries therapeutic challenges, because systemic NAMPT inhibition is known to cause retinal toxicity and potential blindness (30). Therefore, local NAMPT inhibitory strategies or disruption of the tumor-specific signals regulating NAMPT or its downstream consequences need to be carefully considered for potential clinical translation.…”

A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

“…It has been shown that NAMPT inhibition leads to a reduction in NAD + intracellular levels, which can induce apoptosis in cancer cells 2a, 3. However, it has also been reported that targeting of NAMPT might lead to side effects such as blindness 4. A strategy called PhotoActivated ChemoTherapy (PACT) might solve selectivity issues 5.…”