Increasing body weight correlates with loss of ERG in mice with Bardet Biedl Syndrome

Abstract

Purpose: Systemic TUDCA slows development of both retinal degeneration and obesity in a mouse model of Bardet Biedl Syndrome (BBS).We analyzed the relationship between body weight and dark-adapted bright flash b-wave (ERG b-wave) in TUDCA and control BBS mice to determine whether body weight might be used as a surrogate endpoint in treatment trials.

Methods: TUDCA was administered subcutaneously twice weekly to Bbs1M390R/M390R mice at 500mg/kg/dose at 6-8 weeks of age (n=5) or 11 weeks of age (n=5).NaHCO3 was administered to littermate controls at the same ages (n=4, n=3).Body weight and ERG b-wave data were collected at P120 and P180.ERG b-wave amplitudes and body weight were compared between groups using a paired linear regression analysis.The correlation coefficient of change in body weight vs. change in ERG b-wave amplitude between 2 time points was calculated for natural history controls (n=12).

Results: Natural history data for Bbs1M390R/M390R mice demonstrated a very significant negative correlation between body weight and ERG b-wave over time (p=0.0004).Animals treated at 6-8 weeks old with TUDCA had a statistically significantly higher b-wave compared to sham treated (p=0.0022).Body weight was significantly lower in TUDCA treated animals than sham (p=0.0004).The correlation coefficient for difference in weight and b-wave between 2 time points in the TUDCA treated group was -0.7, while the correlation coefficient for these parameters in control mice was 0.46.Bbs1M390R/M390R mice treated at the later age of 11 weeks showed higher ERG b-waves and lower body weight than sham treated, but this was not statistically significant.

Conclusions: This study replicates our previously reported findings of less obesity and better ERG b-wave in Bbs1M390R/M390R mice treated with systemic TUDCA.In addition,it demonstrates an inverse relationship between obesity and ERG b-wave amplitude in untreated mice, and a correlation between changes in body weight and b-wave amplitude in treated mice. As human clinical trials using TUDCA to treat BBS in humans are contemplated, body weight may be considered as a study endpoint since it may be easier to measure and may change more quickly than ERG b-wave. References: Drack et al.,TUDCA slows retinal degeneration in two different mouse models of retinitis pigmentosa and prevents obesity in Bardet-Biedl syndrome type 1 mice. IOVS 2012, 5;53(1):100-6.

Keywords: 695 retinal degenerations: cell biology • 696 retinal degenerations: hereditary • 510 electroretinography: non-clinical