CRISPR activation of PIKFYVE as potential therapy for FIG4 deficiency

Abstract

Abstract/SummaryFIG4 deficiency is the cause of Charcot Marie Tooth type 4J, a neurological disorder characterized by enlarged lysosomes. Our CRISPR activation genome wide screen found that upregulation of PIKFYVE rescued the enlarged lysosome phenotype in cultured cells. To assess PIKFYVE upregulation treatment in vivo, we generated Fig4 deficient mice with CRISPR activation of Pikfyve in neurons. Pikfyve was increased 2 fold in whole brain of CRISPR activated mice. Pikfyve upregulation did not extend the 3 week survival of Fig4 deficient mice. Vacuolization of brain was not rescued. The data demonstrates that a 2 fold increase of Pikfyve is not sufficient to treat Fig4 deficiency. Further testing will be required to determine if a higher increase of Pikfyve can ameliorate the effects of FIG4 deficiency in vivo.