Schnyder Corneal Dystrophy (SCD) is a rare autosomal-dominant genetic eye disease leading to a progressive decrease in visual acuity and blindness. SCD is characterized by bilateral corneal opacification which is given by an excess of free cholesterol and phospholipids.Corneal transplantation is the only available treatment. In order to develop therapeutic interventions that could treat or prevent the disease, a clear understanding of SCD pathogenesis is needed. SCD has been associated to dominant mutations in the human UBIAD1 gene. The role of the SCD mutations in UBIAD1 function and, possibly, in lipid metabolism is unknown. We discovered that the cornea of SCD mice models are affected by oxidative stress and lipid peroxidation. Also, the introduction of SCD mutations in epithelial cells is associated with ferroptosis, a type of programmed cell stress dependent on iron and characterized by the accumulation of lipid peroxides, eventually leading to cell death. Our goal is to confirm that SCD patients are affected by the accumulation of lipid peroxides and ferroptosis in their cornea. Then, by modeling SCD in mouse and human corneal stem cell models we aim to demonstrate that UBIAD1SCD variants are unable to contribute to CoQ10 synthesis and thus provide antioxidant protection for lipids in the plasma membrane. Once validated, the identification of ferroptosis-based mechanisms that cause SCD will lead to the development of novel therapeutic and treatment strategies in the prevention and cure of this corneal dystrophy and possibly others (e.g. drug development and gene therapies).

Una malattia genetica è una malattia causata da anomalie nei geni o nei cromosomi. Nella maggior parte dei casi le malattie geniche sono rare e colpiscono una persona su diverse migliaia o milioni. In questo progetto ci occupiamo di una malattia genica chiamata Distrofia Corneale di Schnyder (Schnyder Corneal Dystrophy; SCD). La SCD è una malattia genetica autosomica dominante caratterizzata da una progressiva cecità dovuta al progressivo accumulo di lipidi (colesterolo e fosfolipidi) nella cornea di questi pazienti. Non esiste attualmente cura se non la rimozione e sostituzione della cornea nei pazienti affetti da questa malattia. La malattia SCD è stata associata a mutazioni del gene UBIAD1. UBIAD1 è una proteina transmembrana la cui funzione è ancora non completamente compresa del tutto. Usando modelli animali ma anche tessuti derivati da pazienti SCD, in questo progetto ci prefiggiamo di studiare i meccanismi molecolari che sono attivati dalle mutazioni SCD presenti nel gene UBIAD1 per capire quali sono i difetti cellulari alla base di questa patologia umana. Lo scopo finale è, quindi, quello di sviluppare delle strategie terapeutiche adeguate (farmacologiche, genetiche e cellulari) per curare i pazienti affetti da SCD.

Weiss, J.S. and A.J. Khemichian, Differential diagnosis of schnyder corneal dystrophy. 2011, S. Karger AG. p. 67-96. Weiss, J.S., et al., Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy. Investigative Ophthalmology and Visual Science, 2007. 48(11): p. 5007- 5012. Mugoni, V., et al., Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell, 2013. 152(3): p. 504-518. Stockwell, B.R., et al., Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 2017. 171(2): p. 273-285. Han, C., et al., Ferroptosis and Its Potential Role in Human Diseases. Front Pharmacol, 2020. 11: p. 239. Lisch, W., et al., Schnyder's dystrophy. Progression and metabolism. Ophthalmic Paediatr Genet, 1986. 7(1): p. 45-56. Dixon, S.J. and B.R. Stockwell, The Hallmarks of Ferroptosis. Annual Review of Cancer Biology,

SCHNYDER CORNEAL DYSTROPHY; SCCD

DIstrofia del Cristallino di SCHNYDER