Nuovo approccio per il trattamento dello Xeroderma Pigmentoso: case report

Xeroderma Pigmentosum (XP) is a rare genetic syndrome characterized by an enzymatic defection in the DNA-repair pathway known as nucleotide excision repair (NER). Patients show extreme sensitivity to sun exposure and a high incidence of skin tumours that strongly invalidate their lifestyle, reducing the life expectancy to a maximum 40 years old. To date, no curative treatments are available for XP patients. Throughout the years, numerous therapeutic approaches have been proposed as an alternative to surgical resection of skin cancers, however, they showed to induce nonspecific mild/severe adverse effects. With the introduction of personalized medicine, alternative methods have been proposed. Among them, the gene therapy and delivery of an exogenous DNA repair enzyme, T4 endonuclease 5 (T4N5), mediated by lipidic nanoparticles. The last approach demonstrated to exert the best performance and to be well tolerated, without inducing any nonspecific/adverse effects. Nevertheless, their efficacy resulted limited by the structural composition of the carrier. The present Ph.D. thesis is based on the characterization of the molecular mechanisms underlying the clinically demonstrated efficacy of an optimized T4N5 liposomal formulation, used in vivo as an alternative treatment for one XPC patient. This analysis showed that the proposed formulation is efficient to rescue many of the intracellular pathways that are recognized as altered by the pathologic status (i.e., P53, Notch1, NF-κB, EGFR) and that are involved in the cancer onset, guaranteeing a safety condition. Moreover, in order to further improve this medical approach, an analogue liposomal formulation has been manufactured to vehicle a newly synthetized peptide (XP-1), corresponding to the sequence of T4N5 able to bind the damaged DNA. The responsiveness of both T4N5 and XP-1 liposomal formulations to UV exposure was in vitro evaluated through the assessment of a cellular model using fibroblasts obtained from the XPC patient. This study allowed to demonstrate that the enzyme and the peptide efficiently rescue XPC cells from UV-induced DNA lesions and restore intracellular checkpoints that are pivotal in the maintenance of skin homeostasis (i.e., cell cycle control, oxidative stress, inflammation, fibrosis and extracellular matrix integrity). Overall, this work suggests that improved liposomal formulations containing T4N5 or XP-1 could be suggested as successful medical devices to counteract the molecular basis of a disease that was incurable for many years.