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Gene Correction of Pompe Disease and Other Autosomal Recessive Disorders via CRISPR and other RNA-Guided Nucleases
Wisconsin Alumni Research Foundation
Gene therapy
Genetic disorders
Hit To Lead or Lead Optimization
• Cas9-ribonucleoprotein-based genome editors can correct two distinct mutant alleles within a single human cell precisely.
• Pompe disease is a rare autosomal recessive genetic disease (mutations from both parent carriers have to be inherited by the offspring to see symptoms) that typically affects children during development but can also present as an adult. Pompe disease is characterized by a lack of functional acid alpha-glucosidase (GAA) enzyme. The lack of GAA leads to a glycogen buildup in cells throughout the body, which results in muscular weakness and wasting. Newborns in which the disease is misdiagnosed rarely survive past one year.
• UW–Madison researchers have developed a complexed CRISPR-Cas system (S1mplex; P170309US01) for treating patients with inherited autosomal recessive conditions. The work focuses on Pompe disease. The inventors identified new guide RNA target sites and repair templates that could be used for gene therapy strategies and cell therapeutic strategies.
• The inventors demonstrated successful editing of fibroblast and induced pluripotent stem cells from three Pompe patients at UW Hospital having heterozygous mutations. Using their complexed CRISPR-Cas technology markedly increased editing precision (18.4- fold) in two different cell lines (HEK and hPSC), easing concerns about off-target effects.
US20200140858A1
Design of efficacious somatic cell genome editing strategies for recessive and polygenic diseases. Nat Commun. (2020)
