FIORI RARI

The Fiori Rari Philanthropic Fund supports both Dr. Stefano Berto’s laboratory at MUSC (USA) and Dr. Chiara Verpelli’s laboratory at the CNR in Milan, which focuses on cellular samples.

Below is the CNR’s scientific project, providing insight into the specific nature of their work.

The CNR Institute of Neuroscience is a center of excellence within the Italian National Research Council, dedicated to studying the nervous system from basic research to translational medicine. The Institute’s mission is to understand the cellular and molecular mechanisms underlying neurological and neuropsychiatric diseases, while promoting the development of new therapeutic strategies. The values guiding the Institute’s work include scientific innovation, interdisciplinary collaboration, methodological rigor, knowledge sharing, and a commitment to improving the quality of life for patients and their families.

‍IL1RAPL2 (Interleukin-1 Receptor Accessory Protein-Like 2) belongs to the IL1RAPL family of synaptic adhesion molecules, closely related to IL1RAPL1, a gene already well-known for its involvement in intellectual disability and autism. Despite this strong structural similarity, the neuronal function of IL1RAPL2 remains largely unexplored, and its contribution to neurodevelopmental disorders is poorly understood. A missense variant identified in a patient provides a unique opportunity to directly assess its pathogenic relevance in a human cellular context.

This project aims to determine whether the IL1RAPL2 p.E624K mutation impairs synaptic development and neuronal function using patient-derived human neurons.

Specifically, we propose to:
· define the impact of the mutation on neuronal maturation and synapse formation;
· identify the molecular pathways altered by IL1RAPL2 dysfunction.

The results of our study are essential for developing therapies for patients affected by this rare and understudied condition.

In contrast, here is the project led by Dr. Berto at the Medical University of South Carolina:

This project aims to study the role of IL1RAPL2 in synaptic function and neurodevelopmental disorders, particularly Autism Spectrum Disorder (ASD) and Intellectual Disability (ID).

‍Objective 1: This will explore how the loss of IL1RAPL2 influences dendritic spine density, synaptic development, and neuronal activity in neurons derived from human induced pluripotent stem cells (iPSCs), using advanced imaging, electrophysiology, and transcriptomic techniques. Furthermore, an ASD-associated mutation will be modeled, and its impact on protein function and neuronal connectivity will be examined.

‍Objective 2: This will utilize a next-generation conditional knockout (cKO) Il1rapl2 mouse model to assess how the loss of IL1RAPL2 alters cortical circuits, dendritic complexity, synaptic transmission, and behavior. Spatial transcriptomics will be employed to map circuit-level alterations in the brain.

‍Objective 3: This will test whether antisense oligonucleotide (ASO) therapy can restore the synaptic and behavioral deficits caused by IL1RAPL2 haploinsufficiency due to the p.E624K missense mutation. The project aims to develop and optimize ASOs to increase IL1RAPL2 expression and evaluate their therapeutic potential in both mouse models and human iPSC-derived neurons, with the goal of offering a targeted strategy to correct synaptic and behavioral dysfunctions associated with IL1RAPL mutations.