Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches.

This study assessed the impact of high altitude residence during pregnancy on parameters of maternal immune and endocrine system function. Urinary catecholamines, and serum cytokines, estriol, and cortisol were assessed during pregnancy in women living at moderate or high altitude. Women residing at high altitude exhibited elevated levels of proinflammatory cytokines only during pregnancy, and tended to have higher levels of catecholamines during pregnancy than women living at lower altitude. These data suggest that the combination of high altitude and pregnancy alters the maternal neural-immune axis in a manner that may predispose women to suboptimal birth outcomes.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of mechanical anisotropy in the kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate the clinical feasibility of Acoustic Radiation Force (ARF) induced peak displacement (PD) measures for both exploiting and obviating mechanical anisotropy in the cortex of human kidney allografts, in vivo. Validation of the imaging methods is provided by pre-clinical studies in pig kidneys, in which ARF-induced PD values were statistically significantly higher (p<0.01, Wilcoxon) when the transducer executing asymmetric ARF was oriented across versus along the nephrons. The ratio of these PD values obtained with the transducer oriented across versus along the nephrons strongly linearly correlated (R2 = 0.95) to the ratio of shear moduli measured by shear wave elasticity imaging (SWEI). On the contrary, when a symmetric ARF was implemented, no statistically significant difference in PD was observed (p>0.01). Similar results were demonstrated in vivo in the kidney allografts of 14 patients. The symmetric ARF produced PD measures with no statistically significant difference (p>0.01) between along versus across alignments, but the asymmetric ARF yielded PD ratios that remained constant over a six-month observation period post-transplantation, consistent with stable serum creatinine level and urine protein to creatinine ratio in the same patient population (p>0.01). The results of this pilot in vivo clinical study suggest the feasibility of: 1) implementing symmetrical ARF to obviate mechanical anisotropy in the kidney cortex when anisotropy is a confounding factor, and 2) implementing asymmetric ARF to exploit mechanical anisotropy when mechanical anisotropy is a potentially relevant biomarker.

Pre-clinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). With regards to pre-clinical studies of AAV-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% factor IX, FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible endpoints in these dogs. This review compares the pre-clinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle and liver -based approaches.

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