Proof of Concept study in Wolfram Mice – Mitochon Pharmaceuticals
Mitochon Pharmaceuticals, Inc., Blue Bell, Pennsylvania, is sponsoring a Proof of Concept (POC) study in Wolfram mice using a mitochondrial target approach to attenuate diabetes, behavioral and functional decline. Mitochon has developed clinical stage (Phase I ready) pharmaceuticals that modulate mitochondrial physiology. These compounds, MP101 and MP201, have shown merit in animal models of vision loss, hearing loss, movement disorders, trauma, neuromuscular/neurodegenerative and metabolic diseases. Stephanie Gebel recommended Dr. Sulev Koks at the University of Tartu, Estonia, who generated the Wsf1 KO mice to the company. Dr. Geisler, CSO of Mitochon, said, “I was delighted to hear Dr. Koks outside the box spirit for embracing new ideas and for seeing the possible merits of our approach for Wolfram”. Dr. Saad Naseer provided Mitochon some guidance to capture critical endpoints as well.
The concept is that endoplasmic reticulum (ER) stress associated with Wolfram Syndrome has a strong detrimental effect on the mitochondria and thus cellular survival. In addition, the abundance of oxidative stress in Wolfram through reactive oxygen species (ROS) production via the mitochondria further creates a hostile environment for cells. Unlike anti-oxidants that attempt to mop up ROSs once they are made, Mitochon’s compounds, MP101/MP201, abolish overt ROS production in the mitochondria, which is a much better starting point, and reduce the burden of mitochondrial calcium overload due to ER stress. Together, these targeted approaches have been shown to prevent cell death. Dr. Geisler says “There are many diseases, such as Alzheimer’s, Parkinson, Huntington, epilepsy, Wolfram, Multiple Sclerosis, etc., that have both ER and oxidative stress issues. Our therapies work by helping the mitochondria to cope with the deleterious effects of ER stress.”
With ER stress, the mitochondria get overburdened with calcium coming from the endoplasmic reticulum. One of the main roles of the mitochondria, besides making energy (ATP), is to store calcium and to keep the cytosol calcium free. The calcium storage capacity of the mitochondria is tremendous, but there is a threshold. When that threshold is exceeded, the mitochondria will self-destruct and leak out all of the calcium into the cytoplasm. The neighboring mitochondria are obligated to take it up, but are already near their threshold, so they self-destruct. Eventually, this cascades into the death of cells such as neurons or myotubes (muscle cell). Reducing ER stress is a great approach, but lowering calcium overload at the mitochondria is critical. Since Mitochon’s compounds (MP101 and MP201) simultaneously abolish ROS production and reduce calcium overload, their targeted effects should lower the burden on mitochondria and preserve cellular health in diseases that exhibit these types of stressors. This has already been shown in models of Huntington’s disease, traumatic brain injury (TBI), and Duchenne Muscular Dystrophy DMD) and the plan is to provide evidence that this approach is useful in Wolfram Syndrome.
Dr. Geisler says, “in a nutshell, we plan to run both compounds (MP101 and MP201) in the Wfs1KO mouse starting at 2-mths of age when diabetes starts to appear. They will be orally dosed once per day for 4-mths until 6-mths of age. An oral glucose tolerance test (OGTT) will be performed each month to monitor changes in glucose flux. At the end of the study, behavior will be monitored for balance and gait. Finally, the pancreas will be removed to examine islet morphology (diameter and number), the liver will be used to measure steatosis, histology on the eyes for retinal ganglion cell (RGC) survival and the optic nerve for demyelination. We expect the study to start in July 2018 and complete in early 2019. We don’t know for sure if it will work, but it seems reasonable! We already have data on preventing hearing loss, vision loss, diabetes, neuroprotection, neuromuscular protection, and calcium overload, so Wolfram looks like a plausible target.”
About Mitochon Pharmaceuticals
Mitochon was founded in 2014 by experienced Pharma executives with the mission to develop treatments for insidious diseases through the modulation of mitochondrial physiology, with applications to neurodegeneration (Huntington’s, Parkinson’s, MS) neuromuscular (Duchenne) and developmental (Wolfram Syndrome) diseases. Mitochon’s lead programs, MP101 and MP201, specifically harnesses the power of the mitochondria to provide broad neural protection. These compounds elicit mild increases in energy expenditure that result in strengthening cellular survival – similar to the positive effects seen with fasting and exercise. These compounds also induce an important neurotrophin, Brain Derived Neurotrophic Factor (BDNF), involved in cognition and neural growth. Mitochon is supported by Ben Franklin Technology Partners Southeastern PA, an initiative of the Pennsylvania Department of Community and Economic Development funded by the Ben Franklin Technology Development Authority. Additional Information: www.mitochonpharma.com
For background information, please see [1-5]
- Feissner, R.F., et al., Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci (Landmark Ed), 2009. 14: p. 1197-218.
- Geisler, J.G., et al., DNP, mitochondrial uncoupling, and neuroprotection: A little dab’ll do ya. Alzheimers Dement, 2017. 13(5): p. 582-591.
- Geisler, J.G., Targeting energy expenditure via fuel switching and beyond. Diabetologia, 2011. 54(2): p. 237-44.
- Wu, B., et al., 2,4 DNP Improves Motor Function, Preserves Medium Spiny Neuronal Identity, and Reduces Oxidative Stress in a Mouse Model of Huntington’s disease. Experimental Neurology, 2017. 293(Mar 28): p. 83-90.
- Khan, R.S., et al., Mitochondrial Uncoupler Prodrug of 2,4-Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis. Oxid Med Cell Longev, 2017. 2017: p. 7180632.
