Our Three-Year Planning (2025-2027) for Research

About 7% of the European population is affected by rare diseases (RDs), 80% of which are of genetic origin. RDs are often chronic, multi-organ and over 50% have a neurological component. For years, the interests of the scientific community have been focused on understanding the molecular causes of RDs. New technological resources are significantly accelerating this process, and the number of RDs with known molecular bases is constantly increasing. Furthermore, a large part of genetic RDs begin in childhood and this has facilitated the systematic collection of information at the onset or during the first years of evolution of the clinical picture. Some examples of neurological and genetic RDs of particular interest to us, however, begin in adulthood and are predictable through genetic testing that allows for both observational and therapeutic research programs aimed at preventing neurodegenerative processes. On the other hand, neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are particularly widespread in adulthood and especially in the elderly, and also in this case it is essential to perform a systematic and continuous collection of data. The understanding of pathogenesis and natural history with multidisciplinary approaches and the application of applied and basic research methods are therefore the new frontiers of scientific research in the field of rare neurological and neurodegenerative diseases.

To better classify neurological MR and neurodegenerative diseases, we will use the most advanced technologies in genomic analysis (genomic arrays and next-generation sequencing), bioinformatics and functional studies. Standardization of the process will increase the probability of obtaining solid results on new molecular markers or new genotype-phenotype correlations. The data validated on large cohorts of patients and subjected to the scrutiny of the scientific community will subsequently be used to expand the diagnostic offer of the Research Hospital. To identify specific disease mechanisms, we will also use cellular models, such as reprogrammed cell lines (iPSC) and organoids, and animal models set up on purpose. These tools will also be used to analyze the effects of specific mutations, identify potential therapeutic targets and develop personalized therapies. Finally, through the implementation of the internal care network, data on the natural history of specific genetic diseases will be collected in order to develop modern tools to address the pediatric-adult transition and develop evidence-based diagnostic-therapeutic paths. At the same time, our care network implementation programs also aim to promote the recruitment of specific populations of patients affected by rare and neurodegenerative neurological diseases in the available protocols, also thanks to collaboration agreements with affected patient organizations.

i) To contribute to the nosology of rare neurological diseases through the description of new phenotypes, genotype-phenotype correlations and the identification of new disease mechanisms. ii) To implement the Research Hospital's molecular diagnostic offering. iii) To facilitate the understanding of the natural history of rare neurological diseases and neurodegenerative diseases to slow down the evolution of the disease. iv) To contribute to the identification of innovative therapies and the development of personalized therapy programs. v) To facilitate patient recruitment in available protocols.

i) Identification of new microdeletion/microduplication syndromes by SNP-array; ii) identification of new disease genes by NGS approaches (WES and WGS); iii) broadening the mutational spectrum of known genetic diseases by Targeted Resequencing; iv) evaluation of the contribution of modifier genes on penetrance, variable expressivity, evolution and progression of specific neurological MR; v) analysis of the functional impact of candidate variants by in silico and in vitro approaches; vi) cellular modeling of rare and neurodegenerative neurological diseases by reprogrammed cell lines (iPSC) from patient fibroblasts and organoids; vii) identification of potential therapeutic targets by integrated in silico, in vitro and in vivo analyses; viii) collection and storage of biological samples (biobanking); ix) systematic collection of data on natural history and clinical presentation at different ages .