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Battaglia M.,San Raffaele Diabetes Research Institute | Roncarolo M.-G.,San Raffaele Telethon Institute for Gene Therapy | Roncarolo M.-G.,Vita-Salute San Raffaele University
Seminars in Immunology | Year: 2011

In type 1 diabetes (T1D), insulin-producing pancreatic β-cells are attacked and destroyed by the immune system. Although man-made insulin is life-saving, it is not a cure and it cannot prevent long-term complications. In addition, most T1D patients would do almost anything to achieve release from the burden of daily glucose monitoring and insulin injection. Despite the formation of very large and promising clinical trials, a means to prevent/cure T1D in humans remains elusive. This has led to an increasing interest in the possibility of using T cells with regulatory properties (Treg cells) as a biological therapy to preserve and restore tolerance to self-antigens. In the present review we will attempt to consolidate learning from the past and to describe what we now believe could in the future become a successful Treg-cell based immune intervention in T1D. © 2011.

Biasco L.,San Raffaele Telethon Institute for Gene Therapy | Baricordi C.,San Raffaele Telethon Institute for Gene Therapy | Aiuti A.,San Raffaele Telethon Institute for Gene Therapy | Aiuti A.,University of Rome Tor Vergata
Molecular Therapy | Year: 2012

γ-Retroviral and lentiviral vectors allow the permanent integration of a therapeutic transgene in target cells and have provided in the last decade a delivery platform for several successful gene therapy (GT) clinical approaches. However, the occurrence of adverse events due to insertional mutagenesis in GT treated patients poses a strong challenge to the scientific community to identify the mechanisms at the basis of vector-driven genotoxicity. Along the last decade, the study of retroviral integration sites became a fundamental tool to monitor vector-host interaction in patients overtime. This review is aimed at critically revising the data derived from insertional profiling, with a particular focus on the evidences collected from GT clinical trials. We discuss the controversies and open issues associated to the interpretation of integration site analysis during patient's follow up, with an update on the latest results derived from the use of high-throughput technologies. Finally, we provide a perspective on the future technical development and on the application of these studies to address broader biological questions, from basic virology to human hematopoiesis. © The American Society of Gene & Cell Therapy.

De Palma M.,Ecole Polytechnique Federale de Lausanne | De Palma M.,San Raffaele Telethon Institute for Gene Therapy | Nucera S.,San Raffaele Telethon Institute for Gene Therapy | Nucera S.,Vita-Salute San Raffaele University
Cancer Discovery | Year: 2012

Acute mobilization of circulating endothelial progenitors has been implicated in tumor resistance to vascular-disrupting agents. In the current issue of Cancer Discovery, Taylor and colleagues provide novel insight into the kinetics of endothelial progenitor mobilization by vascular-disrupting agents in both mouse tumor models and cancer patients. © 2012 American Association for Cancer Research.

Efficient therapeutic protein delivery is a challenging task in several disease contexts and particularly when the CNS is concerned. Different approaches for brain-directed delivery have been thus far investigated, including direct injection of molecules or of their coding information carried by dedicated vector systems within the brain parenchyma or in the ventricular space, intravenous systemic administration of molecules/vectors modified to target and cross the blood-brainbarrier, and exploitation of allogeneic and/or autologous and genetically modified cells as vehicles for the therapeutic of interest. Among these, we here review one of the most promising approaches based on hematopoietic stem cells, taking advantage of lysosomal storage disorders as representative disease setting. © 2012 Bentham Science Publishers.

Battaglia M.,San Raffaele Telethon Institute for Gene Therapy | Stabilini A.,San Raffaele Diabetes Research Institute | Tresoldi E.,San Raffaele Telethon Institute for Gene Therapy
Methods in Molecular Biology | Year: 2012

CD4 +CD25 +FOXP3 + T regulatory (Treg) cells are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. The possibility to use Treg cells for the treatment of T-cell-mediated diseases has recently gained increasing momentum. However, given the limited amount of circulating FOXP3 + Treg cells, efficient methods for their ex vivo expansion are highly desirable. Rapamycin allows for in vitro expansion of murine and human FOXP3 + Treg cells, which maintain their regulatory phenotype and suppressive capacity. Here, we describe in detail the powerful methods for enriching human FOXP3 + Treg cells starting from unfractionated CD4 + T cells or for expanding CD25 +-enriched Treg cells in the presence of rapamycin.

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