Prader–Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). The syndrome is considered the most common genetic cause of obesity, occurring in 1:10,000–1:30,000 live births. Its main characteristics include neonatal hypotonia, poor feeding, and lack of appetite in infancy, followed by weight gain, lack of satiety, and uncontrolled appetite, frequently after the age of 2–3 years. The clinical picture includes short stature, multiple endocrine abnormalities (hypogonadism, growth hormone/insulin-like growth factor-I axis dysfunction, hypothyroidism, central adrenal insufficiency), dysmorphic features, scoliosis, osteoporosis, mental retardation, and behavioral and psychiatric problems. Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake. In fact, PWS subjects die prematurely from complications conventionally related to obesity, including diabetes mellitus, metabolic syndrome, sleep apnea, respiratory insufficiency, and cardiovascular disease. The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. Consequently, dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS. In spite of all available therapeutic tools, however, successful weight loss and maintenance are hardly accomplished. In this context, clinical trials with new drugs have been initiated in order to find new possibilities of a therapy for obesity in these patients. The preliminary results of these studies seem to be encouraging. On the other hand, until well-proven medical treatments are available, bariatric surgery can be taken into consideration, especially in PWS patients with life-threatening comorbidities.

Context and objectivePrader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available.Methods and designMulti-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50–70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures.ResultsAZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion.ConclusionsAZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.

Aurora-A kinase has recently been shown to be deregulated in thyroid cancer cells and tissues. Among the Aurora-A substrates identified, transforming acidic coiled-coil (TACC3), a member of the TACC family, plays an important role in cell cycle progression and alterations of its expression occur in different cancer tissues. In this study, we demonstrated the expression of the TACC3 gene in normal human thyroid cells (HTU5), and its modulation at both mRNA and protein levels during cell cycle. Its expression was found, with respect to HTU5 cells, unchanged in cells derived from a benign thyroid follicular tumor (HTU42), and significantly reduced in cell lines derived from follicular (FTC-133), papillary (B-CPAP), and anaplastic thyroid carcinomas (CAL-62 and 8305C). Moreover, in 16 differentiated thyroid cancer tissues, TACC3 mRNA levels were found, with respect to normal matched tissues, reduced by twofold in 56% of cases and increased by twofold in 44% of cases. In the same tissues, a correlation between the expression of the TACC3 and Aurora-A mRNAs was observed. TACC3 and Aurora-A interact in vivo in thyroid cells and both proteins localized onto the mitotic structure of thyroid cells. Finally, TACC3 localization on spindle microtubule was no more observed following the inhibition of Aurora kinase activity by VX-680. We propose that Aurora-A and TACC3 interaction is important to control the mitotic spindle organization required for proper chromosome segregation.

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A high incidence of glucose metabolism alterations (impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes) has been observed in Prader-Willi syndrome (PWS) (7-40%), particularly after pubertal age and in obese subjects (1). Glucagon-like peptide 1 (GLP-1) receptor agonist (exenatide) and analog (liraglutide) are the new drugs recently introduced for type 2 diabetes that simultaneously reduce appetite and body weight, and their beneficial effects have been reported only in few cases with PWS (2-5). We report, for the first time, the effects of long-term liraglutide or exenatide treatment in six genetically confirmed (3 deletion and 3 uniparental disomy of chromosome 15) (UPD) adult PWS patients (3 males, aged 20.7-37.7 years; all but one obese, BMI 28-57.2 kg/m 2) never treated with growth hormone, affected by type 2 diabetes. All patients were treated at least 12 months with metformin (1,700-3,000 mg/day) and/or gliclazide (30 mg/day) before therapy with GLP-1 agonists/ analogs. The range used for GLP-1 agonists was 1.2 to 1.8 mg/day for liraglutide (4 patients) and 20 mg/day for exenatide (2 patients) (Table 1).