Mitotherapeutix LLC SBIR Phase I Award, July 2020

The prevalence of fatty liver in dairy cows can be as high as 50%.Consequences of fatty liver include decreased reproductive success suppressedimmune functions ketosis retained fetal membranes endometritis displacedabomasum mastitis and milk fever. These disorders cause substantial economic lossesto dairy farmers; however no economically viable treatments exist.Up to half of all transition dairy cows can be in a negative energy balance. To meetnutrient and energy requirements such cows mobilize fatty acids from adipose tissuewhich are then taken up by the liver. This accumulation can lead to fatty liver especiallybecause cows in transition have a lower ability to metabolize fatty acids throughmitochondrial beta-oxidation which is coupled to the mitochondrial electron transportchain (ETC). A key down regulator of the ETC is the MCJ protein (MCJ/DnaJC15 orMethylation-Controlled J protein). We have shown that depression of MCJ expressionresults in increased rate of beta-oxidation in the liver thus reducing levels of fatty acidsand TAG. This occurred without increasing the generation of reactive oxygen species(ROS) and proved safe in a small mammalian model (mice). We reduced expression ofMCJ using an siRNA formulation that is specific for the MCJ mRNA (siMCJ).The goal ofthis proposal is to determine whether or not administration of siMCJ to early post- parturient dairy cows at risk of developing fatty liver can prevent that development of fattyliver in a commercially viable manner (i.e. no clear toxicity and apparently saleable milkproduction is maintained).We expect that transition cows treated with siMCJ will show aclinically significant decrease in fatty liver (a surrogate marker for ketosis due to fatty liver)compared to control transition cows treated with vehicle alone. Milk composition isexpected to remain unaffected by treatment and we expect to see a trend in increasedmilk production in the treated group.We expect our drug (siMCJ) to be affordable enough to be used prophylactically bydairy farmers. We expect a farmer will inject the drug subcutaneously. The cost due fattyliver related ketosis is estimated at about $250 million to the US dairy industry whichincludes losses to subclinical ketosis. There are ~9 million dairy cows in the US of whichabout 3.5 million are at risk. Our drug cost will be ≤ $15 per cow. Average loss to the dairyfarm per cow is ~$225 million/3.5 million or about $70 per cow. We will aim at a price of$20-30/cow. The positive impact on the dairy industry in the US could be considerable.