Mitochondria play a vital role in cellular metabolism. Because of their widespread effects on cellular functions, mitochondrial dysfunction is implicated in a wide range of diseases. As such, mitochondria, the tiny energy factories found in most cells, are prime targets for drug development. But developing mitochondria-targeted drugs has been a daunting task.

Diane Felsen, PhD, is Associate Professor of Pharmacology Research in Urology at Weill Cornell Medicine, where she is Co-Director-together with Dix P. Poppas, MD-of the Institute for Pediatric Urology Research Lab, in New York City. Dr. Poppas is Professor of Pediatric Urology and Chief of the Institute for Pediatric Urology at NewYork-Presbyterian Hospital/Phyllis and David Komansky Center for Children's Health at Weill Cornell Medical Center.

Serendipity

Drs. Felsen and Poppas are researching a highly promising mitochondrial-targeted drug candidate, known as SS-31, which targets the inner mitochondrial membrane (IMM). As Dr. Felsen explained, its discovery was completely serendipitous.

"It was designed for something totally different," she said. "Discovering that SS-31 went into the IMM has led to a new first-in-class group of compounds that can restore cellular bioenergetics."

SS-31 belongs to the Szeto-Schiller (SS) family of peptides. Dr. Felsen's colleague, Hazel H. Szeto, MD, PhD, was researching the ability of one of these peptides, SS-02, to bind to the mu-opioid receptor and accidentally discovered its potential for crossing the blood-brain barrier. Subsequent studies showed that SS-02 could readily cross cell membranes and target the IMM (J Biol Chem 2004;279:34682-34690). Eventually, the peptide analog SS-31 was designed to selectively target the IMM, while having a negligible effect on opioid receptors.

"There are a lot of drugs that are touted as mitochondria-targeted, but they're not particularly useful or effective," Dr. Felsen noted. "SS-31 and this class of compounds are unique."

One of the things that makes these peptides unique is their ability to highly concentrate within the IMM. SS-31 binds selectively to cardiolipin, a phospholipid expressed exclusively on the IMM. Changes in cardiolipin have been associated with age and multiple pathologies, including diabetes, skeletal muscle weakness, neurodegenerative diseases, traumatic brain injury, heart failure and ischemia-reperfusion injury.

Renal Obstruction

Dr. Felsen and her colleagues first demonstrated the effectiveness of SS-31 in the attenuation of renal damage based on a 14-day unilateral ureteral obstruction model in rats (Am J Physiol Renal Physiol 2008;295:F1545-F1553). Ureteral obstruction causes renal damage in two ways: Tubular apoptosis occurs as an early event, followed by inflammation and interstitial fibrosis in response to cytokine and chemokine release from injured tubular cells. Dr. Felsen and her colleagues showed that SS-31 significantly decreased tubular apoptosis and interstitial fibrosis, providing proof of concept that peptides targeting the IMM can protect against obstructive kidney damage.

Renal obstruction occurs in adults for a variety of reasons, and can occur in utero. "For example, some children are born with obstructed systems," Dr. Felsen said. "When that happens, there is a waiting period where the urologist waits to see whether or not the obstruction resolves. There aren't markers to figure out who will resolve and who won't, and there's nothing to ameliorate the damage that is happening while the urologist and the family wait." A drug like SS-31, which has been shown to be safe in adults, might be used during this waiting period. SS-31, as elamipretide, is currently in clinical trials for heart failure and mitochondrial myopathy.

Ischemia-reperfusion injury is also a critical factor in the damage caused by testicular torsion. Current studies in rats are designed to test the efficacy of SS-31 in a torsion model. If these preclinical studies are successful, they could lead to future studies in patients. Timely reperfusion is paramount in reducing the damage caused by ischemia. Dr. Felsen and her colleagues are hoping that SS-31 could be the key to buying that time for patients in need.