Generation of cell lines using the CRISPR-Cas9 system: an opportunity to study mechanisms of neurodegeneration in Rare Diseases and the development of new treatments with impact to the public health system

• Grant number: 19/15369-6
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2020
• End date: July 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Agreement: CONFAP - National Council of State Research Support Foundations
• Principal Investigator: Helena Bonciani Nader
• Grantee: Helena Bonciani Nader
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Alexey V Pshezhetsky ; Gustavo Monteiro Viana ; Leny Toma ; Renan Pelluzzi Cavalheiro

Abstract

Among the rare diseases, mucopolysaccharidoses I and II (MPS I and II) are particularly common in the states of São Paulo and Rio Grande do Sul and are caused by mutations in genes encoding lysosomal proteins (enzymes). The currently available treatments are not curative and are particularly inefficient for the prevention of neurological symptoms. In addition, they cost millions of dollars annually, burdening the public health system of the two states. Therefore, knowledge of the pathogenesis of the neurological disease in MPS becomes important for the development of new, more efficient and cheaper treatments. Taking this into account, this proposal aims to use the gene-editing technology by CRISPR-Cas9 to create neuron lineages with MPS. We will investigate these pathways as well as in the brain of murine models with MPS I and MPS II, pathways that may be altered and may be responsible for the neurological disease observed in the patients, paying particular attention to the activation of the amyloidogenic pathway, since our preliminary results suggest that accumulation of beta-amyloid peptides in animal models of MPS. The creation of lineages will also allow new treatments to be screened / tested in vitro in the future, accelerating the discovery of new molecules. From these results, it is expected that this gene-editing technology can be used to unravel the pathogenesis of rare diseases, as well as provide research for new treatments for several conditions. (AU)