Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 1013 vector genomes per kilogram (vg/kg), 1 × 1014 vg/kg, and 2 × 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day-7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD

Workload of surgeons involved in the treatment of breast cancer

The management of breast disease is becoming a recognized sub-speciality of general surgery. This paper describes the results of a survey undertaken in order to identify consultant general surgeons who would be willing to act as trainers of surgeons who may wish to declare an interest in breast disease. The survey has also given an insight into the workload of surgeons who are involved in the management of both symptomatic and screen-detected breast disease. The questionnaire was sent to all surgeons in England and Wales and to selected surgeons in Scotland and Northern Ireland. The response rate was 51%. The mean number of new cases of breast cancer seen per year by each surgeon was 66 with a range of 2-400. Half the surgeons were involved in the National Breast Screening Programme. The mean number of screening cases referred for biopsy per year was 46 for those involved in the screening programme. Approximately half of the surgeons who undertake breast work spend less than 20% of their time in the subject. The majority (97%) also take emergency admissions in general surgery. Twenty-five per cent carry out breast reconstructions themselves. The breast screening programme has not resulted in an excessive workload but this study has failed to show that the management of breast cancer is in the hands of those with a special interest in the subject