Selective Inhibition of Pathological Mitochondrial Fission to Improve Mitochondrial Function and Inhibit Neurodegeneration and Neuroinflammation in ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the death of neurons in the brain that control our muscles (called motor neurons). ALS is manifested clinically by progressive muscle wasting and paralysis, and individuals with ALS most commonly die of respiratory failure or pneumonia within 3 to 5 years of initial diagnosis. There is no cure for ALS, and two drugs, riluzole and edaravone, are approved to treat ALS. However, these only slow the progress of disease modestly. Given this, there is a strong need to develop new and improved treatment strategies for the ALS patient community. This is a challenging task; with the exception of edaravone, all drug candidates have failed clinical trials for nearly 30 years. At the core of this challenge is the fact that the primary cause of ALS remains unclear. It is hypothesized that a combination of genetic, environmental, and age-dependent factors contribute to the risk of developing ALS. Several genetic mutations have been linked to a small percentage of cases, but even so, the underlying mechanisms by which these ALS pathologies form and the causal relationship between these events and the death of motor neurons are not known. Compounding this, although research has uncovered a number of different cellular processes that are involved in the development of ALS, targeting these with drug candidates has been unsuccessful. Recently, mitochondrial dysfunction has been identified as one such process and has been repeatedly observed in studies of ALS. Mitochondria are organelles within the cell that are responsible for maintaining cellular energy demands and regulating the removal of unwanted and damaging toxic reagents from cells. In a healthy cell, mitochondria exist in extensive networks that are highly dynamic; they undergo coordinated cycles of fusion (connecting two mitochondria into one) and fission (breaking a single mitochondrion into two). These mitochondrial processes are essential to maintaining their cellular function. The delicate balance between fusion and fission is disrupted in ALS. Instead, excessive fission takes place and causes mitochondrial fragmentation. Fragmentation damages mitochondrial networks and impairs mitochondrial function. We have previously identified that, under pathological conditions such as in ALS, two proteins (Drp1 and Fis1) interact to initiate excessive mitochondrial fragmentation, and we hypothesize that targeting Drp1/Fis1 interaction with small molecule inhibitors will improve mitochondrial dysfunction in ALS and may lead to disease-modifying treatments. In previous work, we have designed an inhibitor of this interaction, the P110 peptide, that blocks Drp1/Fis1 interaction in mitochondria and is effective in ALS patient-derived cells and in an ALS mouse model. Since this type of compound, a peptide, is not an optimal drug candidate for humans because it is unstable and not easy to use, our objective in the proposed project is to identify and evaluate novel small molecule mimetics of P110 as potential therapeutic candidates for ALS treatment. We are encouraged by our finding that the parent therapeutic appears to be safe when given to rodents for 5 months and hope that, similarly, a small molecule that mimics P110 will also be found to be safe. We have a strong team to address our objectives and will utilize our experience in drug discovery, drug development, mitochondrial biology, neurology, and ALS modelling. If successful, this research will be the first step in identifying novel drug candidates for further development as treatment for ALS patients. An ALS drug that inhibits excessive mitochondrial fission may slow down disease progression, improve life quality, and ultimately extend the lives of patients suffering from this devastating illness. Since dysfunctional mitochondria have been observed in a broad range of ALS patients, we anticipate treatment with a fission inhibitor will provide
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210203
Entities
People
- Daria Mochly-rosen
Organizations
- Stanford University
- United States Army