Abstract
Loss-function mutations in the ADNP gene are linked to the Helsmoortel-Van der Aa Syndrome (HMVDAS), a complex neurological disorder characterized by autism and intellectual disability. Adnp mutant mice recapitulate key hallmark of ASD including learning deficit, increased anxiety and repetitive behavior. ADNP is involved in brain development, neuroprotection and modulation of the immune system. Despite a clear link exists between ADNP and the immune system, to date the exact role of ADNP in immune cell is unknown, and we ignore the contribution of the immune system to the progression or severity of the HMDAS. We believe that in HMVDAS defective function of Regulatory T cells (a subset of T cells) exacerbate the pathology, and regulatory T cells expansion might improve disease progression. To test our hypothesis, first, we will perform in depth characterization of the molecular and cellular signature acquired by T cells in the mutant mice and in patients blood samples. Next we will use a tailored gene therapy approach to specifically expand Regulatory T cells in the brain and evaluate the effect on the behaviour of the Adnp mutant mice. In closure, this project would allow us to gain a better understanding of the immune changes associated with ADNP deficiency that may provide clues to pathological processes and allow to identify biological markers that enable early diagnosis and treatment of ASD. In addition we will demonstrate the efficacy of Tregs based immunotherapy in ameliorating cognition and behavioral deficits in the Adnp mutant mice and related developmental disorders.
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