Tay–Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α + β) injected at high (1.3 × 10¹³ vector genomes) or low (4.2 × 10¹² vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus–treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + β), and ganglioside clearance was most widespread in the TSD α + β high-dose sheep. Microglial activation and proliferation in TSD sheep—most prominent in the cerebrum—were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.

This study was designed to determine the effect of feeding or fasting of fat or thin ewes on 24-h leptin profiles. Ewes were assigned, based on ultrasonic assessments of last-rib subcutaneous fat measurements, into fat (fat thickness > 1 cm; mean = 1.52 +/- 0.03 cm; range 1.14 to 2.18 cm) or thin (fat thickness < 1 cm; mean = 0.25 +/- 0.03 cm; range 0.03 to 0.84 cm) groups. Fat and thin ewes were then assigned to either fed or fasted (deprived of feed) groups consisting of five ewes per group. Thus, four groups existed and were designated as fat-fed, fat-fasted, thin-fed, and thin-fasted. Fed ewes had ad libitum access to feed throughout the study. Fasted ewes were prohibited access to feed beginning 48 h preceding the experiment. Plasma samples were collected for leptin analysis from ewes every 15 min for 24 h beginning 48 h after the initiation of feed restriction or the congruent interval in fed ewes. Data were subjected to CLUSTER pulse analysis procedures. Profiles of plasma concentrations of leptin were episodic in nature and did not differ in a diurnal manner. Fed ewes had greater mean concentrations of leptin, area under the curve, number of peaks, peak height, peak nadir, and a shorter interval between peaks than fasted ewes (P < or = 0.05). Fat ewes had greater mean concentrations of leptin, area under the curve, number of peaks, peak height, peak nadir, and a shorter interval between peaks than thin ewes (P < 0.02). There also was a tendency for a body condition x treatment interaction for number of peaks (P = 0.073) and interval between peaks (P = 0.056). These results provide evidence that plasma concentrations of leptin are episodic in nature and are influenced by nutritive state and fat thickness over the ribs, but display no circadian variation.

Background/Aims: Growth hormone (GH) is necessary for optimal reproductive efficiency and its secretion is influenced by sex steroids. This study was designed to determine whether kisspeptin-10 (Kp10) could stimulate GH and if gonadal steroids enhance the GH response to Kp10 in cows. Methods and Results: Intravenous injection of Kp10 at 100 or 200 pmol/kg body weight with or without treatment with estradiol cypionate and/or progesterone increased luteinizing hormone (p < 0.01) plasma concentrations. Plasma concentrations of GH were increased following Kp10 in cows treated with estradiol cypionate and/or progesterone (p < 0.05) but not in cows treated with Kp10 without gonadal steroids. Conclusions: These data suggest that reproductive steroids enhance the sensitivity of the somatotropic axis to physiologically relevant doses of Kp10, and support the possibility that Kp10 is an integrator of luteinizing hormone and GH release.