Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia. When administered subcutaneously, ALN-AT3 showed potent, dose-dependent, and durable reduction of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs). In NHPs, a 50% reduction in AT levels was achieved with weekly dosing at approximately 0.125 mg/kg, and a near-complete reduction in AT levels was achieved with weekly dosing at 1.5 mg/kg. Treatment with ALN-AT3 promoted hemostasis in mouse models of hemophilia and led to improved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors. This investigational compound is currently in phase 1 clinical testing in subjects with hemophilia A or B.

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Gold nanorods (GNRs) are commonly used nanomaterials with potential harmful effects on male reproduction. However, the mechanism by which GNRs affect male reproduction remains largely undetermined. In this study, the metabolic changes in spermatocyte-derived cells GC-2 and Sertoli cell line TM-4 were analyzed after GNR treatment for 24 h. Metabolomic analysis revealed that glycine was highly decreased in TM-4 cells after GNR-10 nM treatment while there was no significant change in GC-2 cells. RT-PCR showed that the mRNA levels of glycine synthases in the mitochondrial pathway decreased after GNR treatment, while there was no significant difference in mRNA levels of glycine synthases in the cytoplasmic pathway. High content screening (HCS) showed that GNRs decreased membrane permeability and mitochondrial membrane potential of TM-4 cells, which was also confirmed by JC-1 staining. In addition, RT-PCR and Western blot indicated that the mRNA and protein levels of blood-testis barrier (BTB) factors (ZO-1, occludin, claudin-5, and connexin-43) in TM-4 cells were also disrupted by GNRs. After glycine was added into the medium, the GNR-induced harmful effects on mitochondria and BTB factors were recovered in TM-4 cells. Our results showed that even low doses of GNRs could induce significant toxic effects on mitochondria and BTB factors in TM-4 cells. Furthermore, we revealed that glycine was a potentially important metabolic intermediary for the changes of membrane permeability, mitochondrial membrane potential and BTB factors after GNR treatment in TM-4 cells.

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