Gene therapy for Recessive Dystrophic Epidermolysis Bullosa: effect of the modulation of AGTR1 expression via CRISPRoff system to reduce fibrosis in 3D skin model

• Grant number: 22/12446-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2023
• End date: July 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Roberta Sessa Stilhano Yamaguchi
• Grantee: Daniel Casartelli de Santa Inez
• Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil

Abstract

Epidermolysis Bullosa (EB), widely described by its characteristic formation of blisters and wounds on the skin, is an incurable genetic disease that affects about eleven individuals in every million, and severely impacts the quality of life of its bearer. Among the various subcategories of EB, there is one that stands out for its successive healing and inflammation of the wounds formed on the skin, with alteration of the pro-fibrotic pathways, categorized as Recessive Dystrophic Epidermolysis Bullosa. Thus, there are drugs that aim to reduce the exacerbated fibrosis observed in the disease. However, negative aspects in relation to these drugs indicate the need to develop new treatments, which also target the reduction of fibrosis, a factor that proves to be positive for the health and quality of life of patients. With this in mind, a method that shows promise is the modulation of the expression of genes involved in fibrosis, to reduce the expression of pro-fibrotic genes. To perform this procedure, the molecular tool CRISPR/Cas has been widely used with success, and there are already drugs that employ its use. There are different classes and applications of this tool, however, its standard use involves cutting the DNA strand, which creates stress in the cell. Thus, the use of the CRISPRoff system, which only modulates the expression of the target gene through epigenetic changes, is less harmful and invasive to the cell. Together, the use of the IDLV viral vector (Integrase Deficient Lentiviral Vector), derived from lentivirus but not integrative, points to an efficient and non-hostile delivery to the cell. (AU)