Pharmacological Induction of Mitochondrial Biogenesis for the Treatment of Spinal Cord Injury
Abstract
Over 12,500 new cases of spinal cord injury (SCI) occur in the United States every year, with the majority of injuries occurring in males prior to age 30. SCI can often result in paralysis below the injury site, and as such, sufferers are generally dependent upon healthcare support for the majority of their lifetime. Additionally, patients suffering from SCI often develop further complications including cardiovascular disease, chronic pain and depression, which together, culminate in a decreased lifespan. Currently, patients affected by SCI are without meaningful treatment. The only approved therapeutic is the anti-inflammatory, methylprednisolone, which not only has a variety of negative side effects such as blood clot formation and pneumonia, but has also exhibited only minimal beneficial effects in a fraction of patients, making it no longer the recommended for use post-injury, strongly indicating the importance of the development of more effective therapeutics for the treatment of SCI. In addition to the initial injury to the spinal cord, a resultant cascade of damaging events referred to as secondary injury largely contributes to SCI. The trauma to the spinal cord damages blood vessels in the area, decreasing blood flow and ultimately oxygen delivery. This loss of oxygen leads to mitochondrial dysfunction, which is characteristic of secondary injury. Mitochondria are known as “the powerhouses of the cell,” as they are responsible for the production of the majority of a cell’s energy supply in the form of ATP. ATP is required for neurons to function normally, indicating the importance of restoring mitochondrial function after SCI. While several studies have investigated mitochondria as therapeutic targets for SCI, none have examined the efficacy of enhancing mitochondrial biogenesis (MB), or increasing the number of functional mitochondria. Formoterol is an FDA-approved drug for the treatment of lung conditions such as asthma and our laboratory has previously shown that formoterol can enhance MB and organ recovery following kidney injury. Furthermore, our preliminary data indicate that formoterol also induces MB in the spinal cord, improving vascular integrity, locomotor function and spinal cord damage after SCI. Ultimately, the proposed studies will investigate the therapeutic efficacy of formoterol, an FDA-approved drug with the potential to be repurposed for the treatment of SCI. Successful completion of these studies has the potential to aid not only the patients themselves by restoring function and decreasing injury progression, but also patient caregivers and the healthcare system, as the estimated lifetime cost of care for an individual suffering from SCI is $3 million. The optimal dose and treatment initiation window post-injury will also be determined in these experiments, which will provide essential preliminary data for efficient clinical studies. Furthermore, because formoterol is already approved by the FDA, the time and money needed to repurpose the drug is much less than what would be required for a new compound to reach approval. Overall, the proposed studies could considerably advance the progress of therapeutic treatment of SCI, having a significant positive impact on those suffering from this debilitating and costly condition, and their loved ones.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910175
Entities
People
- Rick G. Schnellmann
Organizations
- United States Army
- University of Arizona