Pilot Treatment of the PEX1-G844D Mouse with Diosmetin

Principal Investigator: Steven Steinberg

We created the Pex1-G844D mouse to model the clinical phenotype found in humans associated with homozygosity for the equivalent PEX1 mutation, PEX1-G843D.   The Pex1-G844D mouse model recapitulates many features of the mild end of Zellweger Spectrum Disorders.  These include elevated tissue levels of C26:0, elevated bile acid intermediates (DHCA and THCA) and retinal pathology associated with cone failure as measured by electroretinograms (ERG).  The purpose of this study would be to treat newborn homozygous Pex1-G844D mice and a control group with the flavonoid diosmetin, a drug shown in a cell culture model to improve peroxisome assembly and recover impacted biochemical pathways in human PEX1-deficient skin fibroblasts harboring one copy of PEX1-G843D.  This study would require six groups of three Pex1-G844D/Pex1-G844D mice- no drug, low dose diosmetin (20mg/Kg/day) and high dose diosmetin (200mg/Kg/day).  The mice would be treated for 6 weeks by intra-peritoneal injection every other day starting at postnatal day 21 (post-weaning).  A blood spot and feces would be collected every two weeks to monitor C26:0-LPC and bile acid intermediate levels, respectively.  At the end of the six week treatment period mice would undergo ERG testing under sedation and then sacrificed.  Eyes would be harvested for immunohistochemical staining to assess retinal morphology.  Lung, spleen and kidney would be collected for lipid extraction and measurement of total lipid %C26:0 and % C26-lysophosphorylcholine; liver would be collected for quantifying bile acid intermediates.