Widespread correction of central nervous system disease after intracranial gene therapy in a feline model of Sandhoff disease.

Sandhoff disease (SD) is caused by deficiency of N-acetyl-ß-hexosaminidase (Hex) resulting in pathological accumulation of GM2 ganglioside in lysosomes of the central nervous system (CNS) and progressive neurodegeneration. Currently, there is no treatment for SD, which often results in death by the age of five years. Adeno-associated virus (AAV) gene therapy achieved global CNS Hex restoration and widespread normalization of storage in the SD mouse model. Using a similar treatment approach, we sought to translate the outcome in mice to the feline SD model as an important step toward human clinical trials. Sixteen weeks after four intracranial injections of AAVrh8 vectors, Hex activity was restored to above normal levels throughout the entire CNS and in cerebrospinal fluid, despite a humoral immune response to the vector. In accordance with significant normalization of a secondary lysosomal biomarker, ganglioside storage was substantially improved, but not completely cleared. At the study endpoint, 5-month-old AAV-treated SD cats had preserved neurological function and gait compared with untreated animals (humane endpoint, 4.4±0.6 months) demonstrating clinical benefit from AAV treatment. Translation of widespread biochemical disease correction from the mouse to the feline SD model provides optimism for treatment of the larger human CNS with minimal modification of approach.

Venous hemodynamic changes during laparoscopic cholecystectomy.

Virchow's triad of venous stasis, vessel wall damage, and hypercoagulability cites three factors that predispose to the formation of venous thrombosis. The pneumoperitoneum created during laparoscopic surgery results in an intraabdominal pressure that exceeds the pressure of venous blood return from the legs. This may alter venous hemodynamics enough to result in venous stasis in the legs, thus increasing the risk of thrombus formation. Duplex ultrasound was used to measure the diameter and venous flow volume of the common femoral vein during laparoscopic cholecystectomy. Measurements were obtained at three different times: after induction of anesthesia but prior to creation of pneumoperitoneum, during pneumoperitoneum, and after abdominal deflation but prior to reversal of anesthesia. After insufflation of the abdomen, the mean cross-sectional area of the common femoral vein increased (0.83 to 1.15 cm2; p = 0.0024) and the venous flow decreased (11.00 to 6.06 cm3/sec; p = 0.0008). After deflation of the abdomen, there was no significant change in cross-sectional area of the common femoral vein, but there was an increase in venous flow (6.06 to 9.94 cm3/sec; p = 0.0005). Abdominal insufflation during laparoscopic cholecystectomy results in dilation of and decreased flow in the common femoral vein. After deflation of the abdomen, flow in the vein returns to baseline levels.