Development of a treatment of Alzheimer based on the editing of the Amyloid Precuror Protein gene with the CRISPR system
Alzheimer’s disease (AD) is characterized by progressive memory lost due to abnormal function and death of neurons. This is due to the accumulation in the patient’s brain of plaques formed by accumulation of Beta-Amyloid peptides (ABeta) produced by successive cutting of the Amyloid Precursor Protein (APP) by the Beta-Secretase (BACE1) and the Gamma-Secretase. A variant of the APP gene has been recently discovered, which reduces the cutting of the APP protein by Beta–Secretase reducing the formation of ABeta and thus preventing development of Alzheimer’s in humans older than 95 years. The goal of this project is thus to prevent or stop the progression of Alzheimer’s by genetically modifying the APP gene using the newly developed CRISPR gene editing system.
The CRISPR system was discovered only 3 years ago and permits specific modifications to a gene. This technology is progressing extremely rapidly with 2500 published articles. Using this CRISPR technology we aim to modify the APP gene so that it contains the naturally occurring variant, which protects against Alzheimer’s. The experiments will initially be done in neurons in culture followed by experiments in a mouse model of the disease.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Most neurodegenerative diseases of aging are due to mutations of one or several genes leading to abnormal function of the brain. This project uses the brand new CRISPR technology, which targets a precise sequence of 20 nucleotides and to correct a specific gene which contains mutations leading to neurodegenerative disease. Therefore once the CRISPR technology has been shown to effectively modify the gene responsible for Alzheimer’s disease, it could also be used to modify other genes responsible for other neurodegenerative diseases.
With this project, we expect to be able to correct the Amyloid Precursor Protein (APP) gene in neurons of Alzheimer’s patients in culture. We will verify that the cutting of the APP protein by the beta-secretase is reduced in the cells in which the gene has been corrected. We also expect to be able to correct this APP gene in the brain of an Alzheimer’s mouse model. We will verify whether this correction prevents the accumulation of amyloid plaques in the brain of these mice and thus prevents the development of the memory problem.