Gaucher’s Disease

Gaucher’s disease (GD), the most common lysomal storage disorder, is caused by lysosomal hydrolase glucocerebrosidase activity deficiency due to a mutation of the GBA gene. Generation of genetically modified animals that recapitulate GD symptoms in patients has been challenging. GBA knockout mice die shortly after birth and point mutation models don’t display phenotype.  Conditional knockout mice display some of the symptoms of GD.

An alternative model is chronic administration of a glucocerebrosidase inhibitor: conduritol β-epoxide (CBE). Daily intra peritoneal administration of CBE for 2-3 consecutive weeks pre-weaning will accumulate GlcCer in the spleen, liver and brain [Stephens et. 1978].  Severity of observed symptoms are linked to CBE dose and age of administration [Vardi et al. 2016].

Body Weight Growth in C57Bl6 Mice Treated with CBE

Figure 1: Chronic i.p. administration of two doses of Conduritol B-epoxide (CBE; 25 and 37.5mg/kg) from post-natal day 8 significantly affects body weight. [Group size n=12 per treatment. Errors bars are SEM].

Life Span Assessment in C57Bl6 Mice Treated with CBE

Figure 2: Assessment of survival rate of C57Bl6 mice under chronic i.p. administration of two doses of Conduritol B-epoxide (CBE; 25 and 37.5mg/kg) from post-natal day 8.

Death occurred only in the highest dose of CBE, 37.5mg/kg, treated animals. [Group size n=12 per treatment].

Longitudinal and Dose Dependent Responses of Mice Treated With CBE on Motor, Ambulatory and Coordination Tasks

Figure 3: (A) Average total distance traveled in the Open Field during the 30 minute test. (B) Reduction in the latency to fall from the Rotarod. [Data are presented as mean ± SEM].

Major Gait Deficit as Early as 20 Days Post 25mg/kg CBE Injection

Figure 4: Gait analysis in PsychoGenics’ proprietary gait platform, NeuroCube®, indicates (A) high discrimination values between the vehicle and the CBE treated group, 20 days post treatment. Sub-categories of gait and paw positioning features also show significant discrimination. Group size n=12 per treatment. (B) Heat map shows paw placement differences between vehicle and CBE treated mice.