Success of siRNA is dependent on the selection of the right target and Mitotherapeutix has identified a key and unique mitochondrial regulator.
The use of siRNA offers key advantages over classical small molecules in the treatment of disease. For example, once a target peptide for treating a disease is identified, siRNA can be rapidly made and tested to validate the target for efficacy and safety within weeks to months. Small molecules can require up to two years for such validation. As a result of this type of advantage, the development of siRNA as a drug modality has achieved a high level of interest from investors and drug companies, with several siRNA drugs being recently approved. An additional advantage of siRNA over classical small molecules is the potential treatment duration that it can provide. This can vary from a week(s) to months and in the case of inclisiran up to six months for one injection.
A key to development of an siRNA drug is the vector that directs the siRNA to the desired location. The first target selected for an siRNA drug was in the liver. The liver is a good target organ for siRNA-based therapies because the hepatocytes naturally and preferentially take up drugs from the blood. This delivery of drugs to hepatocytes can be greatly enhanced when siRNA is encapsulated in lipid nanoparticles (LNP), which also serves to protect siRNA from degradation in the blood. An even more effective method of delivery to hepatocytes is by attaching siRNA to GALnaC.
Mitotherapeutix has identified a unique target for its first program. Our first target is DNAJC15, a gene that is responsible for the production of a peptide MCJ (Methylation Controlled J Protein), which is an endogenous mitochondrial repressor. The key function of MCJ is regulation of mitochondrial energy production. Although MCJ can be found in every cell, there are certain cells and tissues that appear to have a larger presence of MCJ. Three organs that have a high level of MCJ include the liver, the kidney, and the heart. How and why the levels of MCJ are higher in these organs is under investigation; but appears to be related to the dynamic metabolic nature of these organs.
MCJ is a transmembrane protein of the inner mitochondrial membrane of the mitochondria. MCJ is associated with Complex I of the Electron Transport Chain (ETC). The electron transport chain is made up of a series of protein complexes (Complex I,II,III,IV and V) Complex I, III and IV can form a Super-complex under the right conditions which enhances the movement of protons and electrons and ultimately increases the production of ATP while reducing reactive oxygen species (ROS). The reduction of ROS limits potential damage to the cell. When MCJ is removed (knocked out) Complex I, Complex III and Complex IV form a super-complex with the coincident increase in energy and reduction in ROS. The Electron Transport Chain is responsible for production of 90% of the energy generated in the cell.
There are two main sources of “fuel” for the electron transport system. One is derived from the citric acid cycle (CAC) – also known as the TCA cycle (tricarboxylic acid cycle) or the Krebs cycle – which is a series of chemical reactions used to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins, into adenosine triphosphate (ATP) and carbon dioxide. The other is beta-oxidation, which is the catabolic process by which fatty acid molecules are broken down in the cytosol of the mitochondria to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2, which are co-enzymes used in the electron transport chain.
A number of key drugs that are being tested for use in the treatment of NASH and cirrhosis work through the beta oxidation pathway in the mitochondria. Results are encouraging in the modification of fatty liver disease. Mitotherapeutix’s approach siRNA is also seeing an impact in beta oxidation with concomitant changes in steatosis, inflammation, and fibrosis in mouse models.