Abstract Details

Title Preclinical Assessment of TAK-831, a Selective D-Amino Acid Oxidase Inhibitor, in a Genetic Model of Friedreich’s Ataxia (YG8sR)

Topic Movement Disorders

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-005

Objective To determine the preclinical efficacy of TAK-831 in amelioration of motor symptoms in a mouse model of Friedreich's ataxia (FRDA).

Background TAK-831 is a selective and potent inhibitor of D-amino acid oxidase that is being developed for the treatment of Friedreich’s ataxia. YG8sR mice contain 120 intronic GAA repeats and show reduced frataxin mRNA levels and an FRDA-like disease phenotype. The animals show an ataxic phenotype as they age, resulting in progressive behavioral deficits in motor tests such as the beam walk, disruption of glucose homeostasis, and sensory neuron pathology that recapitulates the disease in humans.

Design/Methods Male and female YG8sR mice and Bl/6 controls at 4-5 months of age were tested on the beam walk test. TAK-831 was dosed acutely at 3 mg/kg po with a pretreatment time of 5 hours and assessed on its ability to improve the performance of mice on the beam walk. This dose was also assessed in a chronic dosing (daily po dosing for 14 days) paradigm with a pretreatment time of 5 hours in animals that were 7 months of age. Cerebellar samples were also analyzed to determine changes in D/L-serine concentrations.

Results TAK-831 significantly (p<0.01; ANOVA followed by post hoc Dunnett test) improved motor coordination by assessing the performance of YG8sR mice on the beam walk back to control levels when dosed acutely and chronically. Wild-type animals take approximately 4 seconds to cross the beam, while YG8sR mice take 8-10 seconds. Acute and chronic dosing of TAK-831 equally improved performance of YG8sR animals to 5-6 seconds to cross the beam, which is equivalent to wild-type animals. A significant increase in D/L-serine ratio levels was seen after dosing with TAK-831 (p<0.001 compared to vehicle-treated animals).

Conclusions TAK-831 improves coordination ability in YG8sR mice in a test of motor coordination.

Authors/Disclosures
PRESENTER	No disclosure on file
David Miller	No disclosure on file
	No disclosure on file
Jordi Serrats	No disclosure on file

��ɫ��

��ɫ��