Therapeutic gene editing of T cells to correct CTLA-4 insufficiency.

Heterozygous mutations in CTLA-4 result in an inborn error of immunity with an autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic hematopoietic stem cell transplantation. Here, we designed a homology-directed repair (HDR) gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4+ T cells, and functional studies demonstrated CD80 and CD86 transendocytosis. Gene editing of T cells isolated from three patients with CTLA-4 insufficiency also restored CTLA-4 protein expression and rescued transendocytosis of CD80 and CD86 in vitro. Last, gene-corrected T cells from CTLA-4-/- mice engrafted and prevented lymphoproliferation in an in vivo murine model of CTLA-4 insufficiency. These results demonstrate the feasibility of a therapeutic approach using T cell gene therapy for CTLA-4 insufficiency.

Cheques and challenges: business performance in New Zealand general practice.

INTRODUCTION New Zealand general practice mainly functions as small businesses, usually owned by a single or small group of doctors. Consequently, owners often have to balance the provision of patient care with varying funding priorities, changing patient needs and the pressures of running a sustainable business. Such balancing inevitably leads to tensions developing between these factors. AIM To explore and understand these tensions and responses to them, by examining the business performance measurements used by general practice. METHODS For this study, the unit of analysis and focus were individual practices, but qualitative semi-structured interviews with general practitioners (GPs) and practice managers were used to gather the data. RESULTS All participating practices had some form of governance or board review, where high-level aggregated business performance data were presented. More sophisticated business performance measures were evident in the larger, more developed practices and in practices functioning as community trusts. Examples of such measures included doctor utilisation and efficiency, appraisal of risk, patient satisfaction with services and responses to changes in patient demand. DISCUSSION As the number of general practices based on the traditional model decrease, a corresponding increase is likely in the establishment and development of 'super practices' based on a corporatized, multi-service, single-location model. Consequently, service delivery will become increasingly complex and will drive a need for increased sophistication in how general practice measures its business performance, thus ensuring a balance between high-quality, safe patient care and the maintenance of a sustainable business.

Virological failure and subsequent resistance profiles in individuals exposed to atazanavir.

Few data exist regarding the resistance profile in individuals receiving atazanavir. We found that ritonavir-boosted atazanavir is not associated with the development of primary genotypic resistance in individuals failing this combination, without previous protease inhibitor failure. It is rarely associated with the acquisition of primary mutations in individuals with previous protease inhibitor exposure. This is particularly important because of the increasing use of atazanavir monotherapy, and implies that treatment failure is caused by lack of potency.