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.

Seven Pacific harbor seals with meningoencephalitis associated with Sarcocystis neurona-like protozoa are described. Six of the 7 seals were free-ranging and were found stranded over an 80-km stretch of central California coastline; the other was captive. All had marked to severe nonsuppurative meningoencephalitis, most severe in the cerebellar cortex. Immunohistochemistry for S. neurona antigens was positive on brain tissue in all cases, revealing numerous merozoites as well as developing and mature schizonts, including rosette forms. Electron microscopy performed on 3 animals revealed merozoites and schizonts consistent with Sarcocystis sp., with the absence of rhoptries in merozoites, lack of a parasitophorous vacuole around schizonts, and division by endopolygeny. Serology using western blotting revealed the presence of anti-S. neurona immunoglobulins in the sera of 4 of 5 seals tested. Four animals also had a concurrent mild to moderate nonsuppurative myocarditis; in 1 seal, rare sarcocysts of undetermined species were present within cardiomyocytes.

These data demonstrate a lack of tolerability of PLGA microspheres upon intravitreal injection, and suggest that the size, shape, and/or surface area of PLGA depots are critical attributes in determining ocular toxicity.

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Biaxial fractures of proximal sesamoid bones were common in cadavers of racing Thoroughbreds. Differences between medial and lateral bones for characteristics associated with fracture may relate to differences in fracture pathogeneses for these bones. Osteophytes and vascular channels were common findings; however, fractures were less likely to occur in bones with these features.