Telethon Foundation awards multi-round grant to Simona Lodato

Simona Lodato – Associate Professor at Humanitas University and Group Leader of the Developmental Neurobiology Lab at Humanitas, has been awarded funding through the multi-round grant program of Fondazione Telethon, which supports research on rare genetic diseases. The project focuses on WHIM syndrome (Warts, Hypogammaglobulinemia, Immunodeficiency, Myelokathexis), a rare genetic condition that affects the immune system, causing recurrent infections, as well as brain abnormalities and behavioral disorders.

“WHIM syndrome is caused by mutations in a gene known to regulate the development and function of the immune system, called CXCR4. Recent studies, however, suggest that CXCR4 also directly influences brain development. The goal of our project is to understand how and why,” explains Simona Lodato. “Thanks to Fondazione Telethon, we will specifically investigate the relationship between the CXCR4 gene and the development of the cerebellum, which is crucial for balance, motor coordination, and cognitive and emotional behavior.”

The ultimate aim is to understand how different CXCR4 mutations contribute to the complex behavioral symptoms in patients with WHIM syndrome, with the hope of identifying new therapeutic strategies—not only for WHIM but also for other conditions similarly affecting immune functionality and cerebellum development.

An innovative and multidisciplinary approach

Lodato and her team will use advanced experimental models to reproduce and study mutations in the CXCR4 gene. They will focus on a long-overlooked aspect of this pathology: the impact of the mutation on the central nervous system.

By using high-resolution imaging techniques, such as magnetic resonance imaging (MRI), and genomic and transcriptomic approaches, the project aims to identify the molecular mechanisms underlying structural and functional abnormalities in the cerebellum and to determine whether there is a link between the recurrent infections, typical of WHIM syndrome, and the worsening of brain and behavioral alterations.

Finally, the study will test in experimental models the efficacy of certain CXCR4 antagonist molecules in preventing and reducing the brain defects caused by the mutation. These drugs are already in clinical trials for treating the immunodeficiency associated with WHIM syndrome, but their neurological effects remain largely unknown.

The broader implications of the study, beyond WHIM syndrome

The research funded by Telethon represents a step forward in understanding the complex links between genetics, the immune system, and brain development. The results could have significant impacts, not only for patients with WHIM syndrome.

“This project will improve our understanding of WHIM syndrome while also potentially paving the way for new therapeutic approaches, even for analogous genetic conditions,” says Simona Lodato. “Studying a genetic mutation that simultaneously affects brain and immune system development offers a unique opportunity to develop integrated therapeutic strategies.”