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

Genetic Diseases – Pathophysiology and Gene Therapy of Primary Immunodeficiencies and Lysosomal Storage Diseases

A major research area of the Institute is focused on the pathophysiology and gene therapy of primary immunodeficiencies and autoimmune disorders. Individual projects are focused on ADA-SCID (Adenosine DeAminase-Severe Combined ImmunoDeficiency), Wiskott-Aldrich Syndrome, Chronic Granulomatous Disorder (CGD), Omenn Syndrome, and IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome). A second area aims at developing new gene and cell therapies for Lysosomal Storage Disorders (LSD) that have a major involvement of the central nervous system using hematopoietic and neural stem cells (HSC, NSC). The LSD, we are considering are Metachromatic and Globoid Leukodystrophies (MLD and GLD) and Type I Mucopolysaccharidosis (MPS I). Furthermore, blood disorders of interest at SR-Tiget include β-thalassemia and Hemophilia B.

We have reached different stages in the development of gene and cell therapies for these diseases. For ADA-SCID, we have completed our trial of hematopoietic stem cell (HSC)-based gene therapy based on gamma-retroviral vectors (γRV), reaching >10 years follow-up in the first treated patients. This seminal work has provided an as yet unique evidence of substantial clinical benefit without adverse effects in the field of gene therapy. On October 2010, we entered a strategic alliance with GlaxoSmithKline (GSK), which took exclusive rights to market ADA-SCID gene therapy, committing to further develop product manufacturing to meet the requirements of EMA and FDA for drug registration and marketing.

The successful result of ADA-SCID gene therapy has provided a rationale for extending the HSC-based gene therapy approach to other diseases. We have combined it with the adoption of a powerful new gene transfer platform, based on lentiviral vectors (LV), which improves the efficiency and, likely, the safety of gene transfer. Major achievements from the past years have been the establishment of efficient and safe HSC gene transfer by lentiviral vectors, clinical grade vector manufacturing and the completion of the road map to clinical testing of lentiviral vector mediated HSC gene therapy in patients affected by Wiskott-Aldrich syndrome and Metachromatic Leukodystrophy. Both trials started in 2010. Five and eight patients have already been treated in each trial, respectively. Treatment was safe and well tolerated and all patients are now at home and well, showing stable and remarkably high levels of polyclonal gene marking and therapeutic gene expression in the reconstituted hematopoiesis. For the patients with the longer follow-up there is also a clear evidence of major therapeutic benefit.

SR-Tiget is also developing HSC-based gene therapy for other monogenic diseases such as: β-thalassemia, Type I Mucopolysaccharoidosis, Globoid Leukodystrophy (also known as Krabbe disease) and Chronic Granulomatous Disorder. Clinical trials for beta-thalassemia and mucopolysaccharoidosis type I are expected to start within the next 2 years.

In parallel to the ongoing clinical translation, SR-Tiget scientists have focused their research on innovative studies that are crucial to foster the future translational pipeline, keep up with the constantly evolving scientific and technological advances, ensure a high quality of scientific output in terms of publication and patents, and attract valid young recruits. Thus, we are investigating more deeply the pathophysiological processes that are central to disease pathogenesis, such as immune dysfunction and the development of autoimmunity in primary immunodeficiencies, taking advantage of the panel of diseases being concomitantly investigated both in the clinic and in mouse models, and of the unique opportunity to access patients’ derived tissues before and after gene therapy. We are exploring the therapeutic mechanisms underlying disease correction in order to establish novel dynamic principles of therapy uniquely afforded by gene therapy, such as the advantages of enzyme overexpression and the modalities of its biodistribution in the therapy of Lysosomal Storage Disorders, while at the same time providing new insights into biological processes of tissue homeostasis, such as microglia turnover at baseline and upon myeloablative conditioning, or the impact of disease and inflammation on neurogenesis.

In these severe neurodegenerative disorders, for which we are conducting trials of HSC-based gene therapy, we will also investigate the potential benefit of other approaches, such as direct gene delivery into the CNS and neural stem cell transplantation, and test them also in combination with HSC gene therapy with a view to broaden access to these emerging therapies to more patients, such as already symptomatic MLD patients that are currently excluded from our HSC-based trials. In order to increase the benefits of HSC therapy while at the same time reducing the risks associated with the transplant, we are also testing new methods to mobilize HSC in vivo.
The successful gene transfer into human hematopoietic stem and progenitor cells, as documented in our previous and ongoing clinical trials of HSC gene therapy, offers us an unprecedented opportunity to monitor human hematopoiesis longitudinally with time and throughout all lineages, at the clonal level, taking advantage of the unique genetic marker created by vector insertion in the genome of each cell. We will thus exploit state-of-the-art technologies, human hematochimeric models and our pipeline of clinical trials using different vectors and facing different disease conditions, to investigate long-debated questions on the dynamics of human HSC in normal, stress and disease settings.

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