NOVEL THERAPEUTIC APPROACHES FOR THE TREATMENT OF LYSOSOMAL STORAGE DISEASES
Porto, Caterina (2011) NOVEL THERAPEUTIC APPROACHES FOR THE TREATMENT OF LYSOSOMAL STORAGE DISEASES. [Tesi di dottorato] (Inedito)
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Lysosomal storage diseases (LSDs) are a group of genetic disorders caused by defects in any aspect of lysosomal biology and characterized by the storage of a variety of undegraded molecules in the endosomal/lysosomal compartment. ERT, a major breakthrough in the treatment of LSDs, was successfully translated into the clinical use for some of the most prevalent LSDs, and is currently under study for further applications in other disorders. ERT is based on the concept that recombinant lysosomal hydrolases, mostly enzyme precursors, manufactured on a large scale in eukaryotic cell systems, by interacting with the mannose-6-phosphate or mannose receptors are internalized by cells and tissues through the endocytic pathway and targeted to lysosomes. In the lysosomal compartment they are activated and can replace the function of the mutated defective hydrolases. Although ERT proved to be highly beneficial in some diseases, or in subsets of patients with specific diseases, a number of problems related to its efficacy remain unsolved, including bioavailability of recombinant enzymes, the existence of “sanctuaries” in which corrective enzyme levels are difficult to achieve, and the presence of cellular abnormalities triggered by storage which interfere with ERT efficacy .These limitations point to the need to identify alternative therapies or to improve the efficacy of existing therapy. In this thesis I have studied two models of lysosomal disorders, Pompe disease (PD) and Fabry disease (FD). The general aim of the project of my thesis is to identify novel strategies for the treatment of LSDs, in particular Pompe disease, that may translate into improved efficacy of the existing therapies for these disorders. The approaches that has been evaluated in the project were based on the use of small molecule drugs. The first aim of the project was focused on the implementation on PCT in PD. We expect that the availability of more specific, non-inhibitory chaperones that interact with different non- catalytic protein domains, will expand the fraction of GAA gene mutations responsive to PCT and display increased synergy with rhGAA. The second aim of project is focused on the evaluation of therapeutic protocols based on the combination of PCT and ERT. To this end I have studied the synergy between PCT and ERT in PD and in Fabry disease (FD). Finally, I am currently studying the mechanism underlying the synergistic effects between ERT and PCT.
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