Mitochondria, often described as the “powerhouse of the cell”, are responsible for approximately 90% of energy production in human cells.1 These “powerhouses” are found in all human cells other than mature red blood cells.2 Mitochondria produce energy through the conversion of food into adenosine triphosphate, or ATP.2 This happens through a series of reactions, controlled by the electron transport chain, within the inner folds of the mitochondria.2 In normal mitochondria, the inner mitochondrial membrane is highly folded, creating curves, called cristae.3 The cristae house the electron transport chain, which is composed of five protein complexes responsible for mitochondrial ATP production.3 Cardiolipin, a phospholipid found within the inner mitochondrial membrane, is responsible for establishing the cristae architecture and optimizing the function of ATP generating machinery, including the electron transport chain.4
Dysfunctional mitochondria can have an impaired ability to produce ATP and can generate increased levels of reactive oxygen species, or ROS, a major contributor to oxidative stress.2 Although low levels of ROS can be important signaling molecules in the cell, high levels of ROS can damage proteins and membrane lipids within the cell. Cardiolipin in particular is highly susceptible to oxidative damage, which can result in disrupted mitochondrial structure and a cycle of increasing ROS generation that can lead to the inflammation, fibrosis, senescence and cell death implicated in many human diseases.5
Mitochondrial dysfunction is commonly observed across both common and rare diseases. Contributors to mitochondrial dysfunction can include genetic mutations, the aging process, environmental factors, or a combination thereof. These impairments can affect a number of different organ systems, especially those with high energetic demands such as heart, eye, brain, kidney, and skeletal muscle10-12. Stealth is focused on mitigating mitochondrial dysfunction in rare diseases associated with cardiomyopathy, Barth syndrome, and Leber’s hereditary optic neuropathy7-8, as well as a wide range of common age-related diseases, such as dry age related macular degeneration.9-10
Healthy & Unhealthy
Our lead investigational product candidate, elamipretide, is a peptide compound that readily penetrates cell membranes, and targets the inner mitochondrial membrane where it binds reversibly to cardiolipin.13 In preclinical or clinical studies, we have observed that elamipretide increases mitochondrial respiration, improves electron transport chain function and ATP production and reduces formation of pathogenic ROS levels.13-19 This elamipretide-cardiolipin association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function.13 Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress.13 We are investigating elamipretide in late stage clinical studies in three primary mitochondrial diseases — rare diseases with cardiomyopathy, Barth syndrome and Leber’s hereditary optic neuropathy – as well as a clinical study in dry age-related macular degeneration.