Novel Mitochondrial Targeting Nitroxides for Radioprotection and the Treatment of Associated Pathologies

Free radicals and other reactive oxygen species (ROS) have devastating consequences in living tissue, damaging mitochondria and leading to toxicity and cell death. Irradiation from the sun’s damaging UV rays, radiotherapy for cancer, or exposure to a nuclear accident is the most well-known source of ROS in the body; however, some metabolic processes are responsible for ROS production as well. In particular, faulty fatty acid oxidation (FAO) genes cause a host of disorders due to overproduction of free radicals, such as liver, cardiac, and muscle dysfunction that have no cure and require lifelong management. Traumatic bone injury is another source of free radicals in the body, leading to delayed healing and non-union of bone, especially in patients with preexisting conditions like diabetes or hypertension. Nitroxides are a class of compounds that act as electron and radical scavengers and are effective at mitigating the damage caused by ROS via redox cycling mechanisms, but they pose their own significant problem: at a high enough concentration to accumulate effective amounts in the mitochondria, nitroxides are toxic themselves. In order to combat the destructive capacity of reactive oxygen species in tissue, these agents must be targeted to mitochondria.  

Description

JP4-039 is a next-generation antioxidant derived from predecessors XBP-5-131 and 4-amino Tempo (4-AT), JP4-039 is a Gramicidin S (GS)-derived nitroxide that is highly selective for mitochondria, proven to be effective against oxidative stress caused by free radicals and other ROS and safe for surrounding tissues. Targeting allows mitochondrial concentration to be increased 1,000x compared to non-targeted nitroxides, while decreasing associated tissue concentrations by the same factor and eliminating potential side effects and toxicity. Additionally, delivery of JP4-039 does not depend on or affect mitochondrial membrane potential, and JP4-039 can also target de-energized and damaged mitochondria while not impairing healthy mitochondrial function. JP4-039 has shown to be effective as a radioprotectant if administered prior to exposure to irradiation, as well as mitigating effects if administered after exposure. It allows for selective protection of healthy tissue for targeted tumor radiotherapy. Further, JP4-039 is effective as an electron and radical scavenger for byproducts of FAO disorders, and has been shown to speed bone healing by the same process. It can be administered orally or as a topical emulsion, and thus is non-invasive and economically feasible.

Applications

• Broad applications for skin health and anti-aging
• Protects against total or partial body irradiation and provides for post irradiation protection
• Bone healing after injury
• Treatment for fatty acid oxidation disorders or respiratory chain metabolic conditions

Advantages

• Specifically targeting to mitochondria improves effectiveness while lowering required dose, decreasing toxicity and limiting side effects
• Topical and oral applications are non-invasive and economically feasible
• Effective if administered both before or after exposure
• Allows for selective protection of healthy tissue

Invention Readiness

Pre-clinical validation in multiple animal models Additional indications under development

IP Status

https://patents.google.com/patent/US20110172214A1; https://patents.google.com/patent/US20120252733A1; https://patents.google.com/patent/US20190210969A1; https://patents.google.com/patent/US20140018317A1; https://patents.google.com/patent/US20190142893A1

Related Publication(s)

Brand, R. M., Epperly, M. W., Stottlemyer, J. M., Skoda, E. M., Gao, X., Li, S., Huq, S., Wipf, P., Kagan, V. E., Greenberger, J. S., & Falo, L. D., Jr. (2017). A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage. Journal of Investigative Dermatology, 137(3), 576–586. https://doi.org/10.1016/j.jid.2016.09.033

Berhane, H., Shinde, A., Kalash, R., Xu, K., Epperly, M. W., Goff, J., Franicola, D., Zhang, X., Dixon, T., Shields, D., Wang, H., Wipf, P., Li, S., Gao, X., & Greenberger, J. S. (2014). Amelioration of Radiation-Induced Oral Cavity Mucositis and Distant Bone Marrow Suppression in Fanconi Anemia Fancd2–/– (FVB/N) Mice by Intraoral GS-Nitroxide JP4-039. Radiation Research, 182(1), 35. https://doi.org/10.1667/rr13633.1

EPPERLY, M. W., SACHER, J. R., KRAINZ, T., ZHANG, X., WIPF, P., LIANG, M., FISHER, R., LI, S., WANG, H., & GREENBERGER, J. S. (2017). Effectiveness of Analogs of the GS-Nitroxide, JP4-039, as Total Body Irradiation Mitigators. In Vivo, 31(1), 39–44. https://doi.org/10.21873/invivo.11022

Greenberger, J., Kagan, V., Bayir, H., Wipf, P., & Epperly, M. (2015). Antioxidant Approaches to Management of Ionizing Irradiation Injury. Antioxidants, 4(1), 82–101. https://doi.org/10.3390/antiox4010082