Oligodendrocyte progenitor cell-based therapy in a primary autosomal recessive microcephaly-17 (MCPH17) preclinical model: optimization and mechanisms

Primary autosomal recessive microcephaly-17 (MCPH17) is a genetic form of microcephaly caused by mutations in the CIT gene. Depending on the mutation, MCPH17 patients show neuroanatomical alterations and functional defects, including seizures, ataxia and intellectual disability. A MCPH17 mouse model (i.e. the Cit-k KO mouse) is available and recapitulates the features of the pathology. So far, research on MCPH17 has been exclusively concentrated to the neurogenesis/neuronal defects associated with CIT mutations. Yet, in recent studies in MCPH17 mouse models and patients, we found significant alterations in non-neuronal cells, i.e. oligodendrocytes, and demonstrated that these cells are affected independently of neurons and contribute per se to the pathology. In line with this, we also found that restoring the oligodendrocyte population via cell transplantation positively impacted on the cortical neuronal/circuit maturation, on the behavioral phenotype and on the lifespan of Cit-k KO mice. This strongly suggested that this strategy might be further optimized to design an oligodendrocyte-based cell therapy and/or to gain insights on novel pharmacological targets for the treatment of MCPH17. Thus, here we propose a project aimed at: 1. optimizing the outcome of mouse OPC transplantation in Cit- k KO mice; 2. unveiling the neurophysiological and molecular bases of the effects of an optimized OPC transplantation strategy, to set the stage for drug discovery. The outcomes of our project are expected to have a translational relevance, informing new approaches for the treatment of MCPH17 and possibly of other genetic microcephalies sharing pathogenetic mechanisms and features.