The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)

Immune Responses – Liver-directed Gene Transfer and Tolerance Induction

We continue to investigate the potential of in vivo gene delivery to treat systemic diseases such as Hemophilia B and Mucopolysaccharidoses, capitalizing on the intriguing properties of a novel hepatocyte-targeted lentiviral vector platform that was previously developed and shown to establish stable gene transfer and provide long-term therapeutic benefit in the small as well as large animal model of Hemophilia B. Yet, as we face the realm of in vivo delivery, innate anti-viral responses and transgene-directed adaptive responses represent major hurdles to be overcome for stable and successful gene therapy. Taking advantage of the highly complementary expertise available in our Institute, we will continue to investigate the mechanisms underlying the tolerogenic response triggered by our hepatocyte-targeted vectors, and exploit it to provide proof-of-principle of novel strategies overcoming pre-existing immunity to protein replacement therapy or preventing the development of autoimmune disease. In parallel, we will exploit the manipulation of the different types of T-regulatory cells being characterized in our Institute, such as naturally occurring Treg cells and adaptive type 1 Tr cells, to generate homogeneous populations of Ag-specific T-regulatory cells T-regulatory cells by pharmacological or gene transfer approaches, and potentially combine vector- and cell-based approaches to establish transgene-specific tolerance in humanized mouse models of gene therapy and cell transplantation.

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