A novel therapeutic to address fatty liver in post-parturient dairy cows

Recipient Organization
MITOTHERAPEUTIX LLC
400 FARMINGTON AVE
FARMINGTON,CT 060321913

Performing Department
(N/A)

Non Technical Summary
The prevalence of fatty liver in dairy cows in transiftion can be as high as 50%, whichcauses substantial economic losses to dairy farmers. No economically viable treatments exist.We are developing siMCJ drug to treat the early post-parturient dairy cows from developing fatty liver. Milk composition is expected to remain unaffected by treatment and we expect to see a trend in increased milk production in the treated dairy cows. We expect our drugto be affordable enough to be used prophylactically by dairy farmers and to have considerable positive impact on the dairy industry in the US.

Animal Health Component

60%

Research Effort Categories

Basic

10%

Applied

60%

Developmental

30%

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
311	3410	1060	100%

Knowledge Area
311 - Animal Diseases;

Subject Of Investigation
3410 - Dairy cattle, live animal;

Field Of Science
1060 - Biology (whole systems);

Keywords

dairy cow

fatty liver

ketosis

Goals / Objectives
The goal of this proposal is to determine whether or not administration of siMCJ to early post-parturient dairy cows can prevent development of fatty liver diseasein a commercially viable manner (i.e., no clear toxicity and apparently saleable milk production is maintained).

Project Methods
We'll design and have siMCJ synthesized. The siMCJ will be formulated as lipid nano particle and will be injected (iv) to dairy cows in transition, which are susceptiable developing fatty liver diseases (LFD). Administration of siMCJ should lead to down regulation of MCJ expression in liver, and prevent or reduce development of LFD.

Progress 09/01/20 to 02/28/23

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? While we were planning on injecting the cows to procede with and conclude the study, the PI, Dr. Testroet, ran into some personal challenges and became unavailable to continue the study. Neither we nor UVM were able to find a suitable replacement. We therefore had to discontinue a potentially promising study.

Publications

Progress 09/01/22 to 02/28/23

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? While we were planning on injecting the cows to procede with the study, the PI, Dr. Testroet, ran into some personal challenges and became unavailable to continue the study. Neither we nor UVM was unable to find someone suitable to take his place. We herefore had to discontinue a potentially promising study.

Publications

Progress 09/01/21 to 08/31/22

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The postdoc on the project was trained in the techniques used in the above mentioned study. How have the results been disseminated to communities of interest?An article was published in Animals (Basel)2023 Mar 20;13(6):1101.doi: 10.3390/ani13061101 What do you plan to do during the next reporting period to accomplish the goals?We are using the siMCJ which is a perfect match for human siMCJ and test it in a calf. We are going to examine for the knock down of MCJ by investigating the hepatocytes and looking for the knock down using the liver biopsies of the calf. We are planning to use 2 calves per dose and test it with 2 doses and a control. We will have a control siRNA, 1 milligram/kg and 3 milligram/kg. Testing in the calves will allow us to select one dose for testing in the cow. Dosing will be critical to the potential success of this treatment because the cost of the treatment needs to low enough to make it economically viable.

Impacts
What was accomplished under these goals? Dr. Testroet has carried out initial studies to show the presence of MCJ in cows to support the work ongoing in this grant. The article below was filed and published March 30, 2023. In Vivo and In Vitro Expression of iC1, a Methylation-Controlled J Protein (MCJ) in Bovine Liver, and Response to In Vitro Bovine Fatty Liver Disease Model Shanti Choudhary 1, Michelle LaCasse 1, Ratan Kumar Choudhary 1 , Mercedes Rincon 2, Donald C. Beitz 3 and Eric D. Testroet 1,* Simple Summary: Fatty liver disease (FLD) is a common metabolic disorder of high-milk-yielding cows. Though FLD has been a common disorder of the cow for a considerable period, its molecular mechanism and novel strategy to prevent or mitigate economic losses are less explored. In this study, we, for the first time, showed expression of mitochondrial complex 1 inhibitor (iC1) in bovine liver in situ and established in an vitro model for studying FLD. The role of iC1 in cows should be analogous to its roles in mice and humans and may find application in the etiology and pathology of bovine FLD.

Publications

Type: Journal Articles Status: Accepted Year Published: 2023 Citation: In Vivo and In Vitro Expression of iC1, a Methylation- Controlled J Protein (MCJ) in Bovine Liver, and Response to In Vitro Bovine Fatty Liver Disease Model Shanti Choudhary, Michelle LaCasse, Ratan Kumar Choudhary, Mercedes Rincon, Donald C. Beitz and Eric D. Testroet In Vivo and In Vitro Expression of iC1, a Methylation-Controlled J Protein (MCJ) in Bovine Liver, and Response to In Vitro Bovine Fatty Liver Disease Model Shanti Choudhary, Michelle LaCasse, Ratan Kumar Choudhary, Mercedes Rincon, Donald C. Beitz and Eric D. Testroet Animals (Basel) 2023 Mar 20;13(6):1101. doi: 10.3390/ani13061101 PMID: 36978641

Progress 09/01/20 to 08/31/21

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals?We are using the siMCJ which is a perfect match for human siMCJ and test it in a calf. We are going to examine for the knock down of MCJ by investigating the hepatocytes and looking for the knock down using the liver biopsies of the calf. We are planning to use 2 calves per dose and test it with 2 doses and a control. We will have a control siRNA, 1 milligram/kg and 3 milligram/kg. Testing in the calves will allow us to select one dose for testing in the cow. Dosing will be critical to the potential success of this treatment because the cost of the treatment needs to be low enough to make it economically viable.

Impacts
What was accomplished under these goals? The goal is to produce a product which has positive impact on cows to reduce the fatty liver disease. Dr. Testoret believes that the level of fatty liver is much higher than previously thought and therefore the problem is much greater than initially estimated. We have been working on MCJ in mice, rats and initiated studies in non-human primates. The outcome of these studies has helped us to understand the effect of MCJ and we plan to initiate studies in cows now. We have selected the sequence of siMCJ for cows which is a perfect match to the human siMCJ and plan on testing it first in calves and then in cows.

Publications