Ribosomal pathologies: mechanistic therapy of Shwachman-Diamond syndrome and prevention of malignant complications due to stem cell manipulation

Under the definition of ribosomopathies, we identify inherited monogenic diseases characterized by the loss of functionality of ribosomes, the intracellular factories dedicated to the synthesis of proteins. Ribosomopathies present with symptoms affecting various tissues, including a reduced function of the bone marrow with consequent lack of neutrophils, and a high risk of tumors of the hematopoietic line. Schwachman-Diamond syndrome is caused by loss of function of the SDS gene. Partial loss of the SDS gene causes impaired ribosome function. A significant number of genetic and cellular studies have unequivocally demonstrated that the modification of the biochemical activity of the eIF6 protein can "cure" the defects caused by loss of SDS. In recent years, our laboratory has produced several molecules capable of modifying the function of eIF6 and, potentially, restoring the function of the SDS gene. In this study we propose a comprehensive cost-benefit analysis of manipulating the molecular activity of eIF6 through the compounds that we have developed in the laboratory. The analysis of the molecular effects of eIF6 modulators will be accompanied by the verification of alternative strategies aimed at recovering the functionality of the SDS protein. Finally, we will verify if the eIF6-activity modulation strategy is able to restore the normal function of bone marrow stem cells, without causing side effects. Overall, our study could lay the foundations for a rational and personalized therapeutic intervention for Schwachman-Diamond syndrome