Institute for Transfusion Medicine and Gene Therapy

Group Leader Dr. Claudio Mussolino

The goal of the research group “Genome and Epigenome Editing” is to further develop and apply designer nucleases and epigenome modifiers for achieving precise modification of the cellular genome and/or epigenome. We seek to use these technologies to tackle chronic and acquired immunodeficiencies as well as cancer.

Patients with congenital and acquired immunodeficiencies suffer from frequent and severe infections. The therapeutic options for these patients include transplantation of blood stem cells collected from a suitable donor, to replace the defective immune system with a healthy one provided by the donor stem cells. However, allogeneic transplantations still pose safety concerns because of the potential severe side effects, such as graft-versus-host disease. Our goal is to develop more efficient gene editing platforms to precisely correct the genetic defect (i.e. the mutation) directly in the patient stem cells. Autologous cells, upon correction, can be transplanted back to the patient thus avoiding the risks associated with allogeneic transplantation. However, for acquired immunodeficiency due to HIV infection, this strategy is not suitable because the virus would infect the new immune system again. In this context, we aim at using genome and epigenome editing strategies to confer new characteristics to the blood stem cells of affected patients as the ability to resist HIV infection. Since the virus enters the target cells (T cells, macrophages) via binding to specific co-receptors, our goal is to use genome and epigenome editing to inactivate the genes encoding for these co-receptors and render the edited cells resistant to HIV infection prior transplant.

The concept of providing new features to the human immune system can be also explored in the context of cancer therapy. Indeed, even a properly functional immunity sometimes fails to recognize aberrantly proliferating cells which may give rise to malignancies. Editing the genome of T cells to express a chimeric antigen receptor (CAR) recognizing tumor-specific antigens can instruct the T cells to recognize and eliminate tumor cells. Since CAR T cells can be hampered by tumor-induced exhaustion, we aim at using epigenome editing technologies to render them resistant to inhibitory signals derived from the tumor microenvironment.

Our group has established genome and epigenome editors based on TALEs (transcription activator-like effectors) and CRISPR/Cas platforms. We apply cutting edge techniques and genome wide approaches to thoroughly evaluate efficacy and safety of the strategies described. Our long-term goal is to develop novel therapeutics for patients suffering from immunodeficiency or cancer and we aim at adapting these methodologies to other congenital disorders of the immune system.

A complete list of Dr. Mussolino’s publications can be found to this LINK.