Use of CD19-targeted Immune Modulation to Eradicate AAV Neutralizing Antibodies.

Neutralizing antibodies (NAb) against adeno-associated virus (AAV) represent a significant obstacle to the efficacy of systemic recombinant AAV vector administration or re-administration. While there are some promising preclinical immunomodulation strategies in development, insights into which B cell subsets and compartments maintain persistent AAV NAb may define the optimal eradication strategy. Given the limited success of CD20-directed monotherapy in previous studies, we hypothesized that CD19-directed approaches that extend targeting into the plasma cell compartments may improve AAV NAb eradication.

Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice.

Durable factor VIII expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus-mediated gene therapy. Trials with initially normal factor VIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable expression inadequate to restore normal hemostasis. Here we demonstrate that male mice recapitulate expression-level-dependent loss of factor VIII levels due to declines in vector copy number.

Overcoming Hemophilia A Gene Therapy Limitations with an Enhanced Function Factor VIII Variant.

Durable factor VIII (FVIII) expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus (AAV)-mediated gene therapy. Trials with initial normal FVIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable FVIII expression inadequate to restore normal hemostasis. Here we demonstrate that mice recapitulate FVIII expression-level-dependent loss of plasma FVIII levels due to declines in vector copy number.

Macrophage and adipocyte interaction as a source of inflammation in kidney disease.

In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized.

Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness.