![]() ![]() PH1 mice were treated with D10A-SaCas9 nickase mutants and two gRNAs previously tested efficient for the WT SaCas9. Our approach to decrease off-target modifications was to use a nickase Cas9 combined with two gRNAs targeting nearby regions on the opposite strand. Nevertheless, concerns regarding CRISPR/Cas9 off-target effects should not be underestimated. Recently, AAV8-CRISPR/Cas9-mediated in vivo SRT was shown to greatly diminish GO expression, resulting in urine oxalate reduction and prevention of kidney damage. The inhibition of glycolate oxidase (GO), the enzyme implicated in the synthesis of glyoxylate (precursor of oxalate), has been proven to be an efficient substrate reduction therapy (SRT) to treat PH1. The only curative treatment is liver transplantation, thus, new therapies are required. Consequently, oxalate is overproduced in the liver and accumulated in kidneys causing life-threatening renal damage. Primary hyperoxaluria type 1 (PH1) is a rare genetic metabolic disorder associated with mutations in AGXT gene, causing hepatic alanine-glyoxylate aminotransferase (AGT) deficiency. 4: Harvard Medical School, Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. 3: Cell Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Centre for Biomedical Research on Rare Diseases (CIBERER). 2: Hospital Universitario de Canarias, Universidad La Laguna, Tenerife, Spain. L Torella 1 I Raimondi 1 A Vales 1 C Olague 1 A Abad 1 J R Rodriguez-Madoz 3 M Huarte 1 E Salido 2 G Gonzalez-Aseguinolaza 1 N Zabaleta 1 4ġ: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Paired-nickase S.aureus Cas9 system is an efficient and potentially safer in vivo treatment for Primary Hyperoxaluria Type 1
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