Nephro-Safe

Highlights

• Acute kidney injury causes over 2 million deaths in the USA, and treatment costs are over $24 billion.
• A way to selectively target the kidney to protect against multiple forms of acute kidney include oral dicarboxylic acid 8 (DC₈).
• We have designed and patented a novel formulation of DC₈ to treat acute kidney injury.
• Recipient of $35,000 PInCh Award.

Problem

Kidney injury most commonly occurs in the hospital settings. The major causes are ischemia (shock, trauma, transplantation), nephrotoxins (chemotherapy agents) or sepsis. The annual hospitalization cost of acute kidney injury (AKI) in the USA is approximately $24 billion and causes over 2 million deaths.

While the injured kidney may initially recover, the patients are at a higher risk for subsequently developing chronic kidney disease, which has an additional cost of $100 billion per year in the US. Other times, the acute injury is so severe that there is no kidney recovery, and ultimately the patient progresses to end stage renal disease requiring dialysis and transplantation.

AKI treatment of simple supportive care has remained unchanged for decades. There are no therapies that stop, inhibit, or reverse the kidney injury, and there are no available interventions to decrease the risk of progression to chronic kidney disease, thereby dramatically reducing life expectancy.

Solution

One of the hallmarks of kidney injury is damage to the critical working units of the kidney, known as proximal tubules. The heavy workload of proximal tubules takes a lot of cellular energy. When these energy demands are not met, the proximal tubules get injured and can die – this is the basis of acute kidney injury.

Our solution is unique – we have found a special type of fatty acid known as dicarboxylic fatty acids that can be rapidly and efficiently metabolized by the kidney to produce energy, even under conditions of limited oxygen supply (such as during cardiac surgery). This re-energizes cells in the proximal tubule, and protects against kidney injury.

To expand DC₈ into a proven therapeutic, we need to 1) optimize its timing and dosage to determine how long it takes to achieve protection against kidney injury; 2) determine if the utilization of our uniquely designed Tri-DC₈ can lead to improved protection; and 3) test the utilization of this therapy in other common hallmarks of AKI, including nephrotoxic and sepsis models.

Team

• Sunder Sims-Lucas PhD, Pitt Division of Nephrology, serving as the Principal Investigator and acute kidney injury expert.
• Jacqueline Ho MD, Pitt Division of Nephrology. Pediatric nephrologist overseeing animal health and well-being post-surgery.
• Eric Goetzman PhD, Pitt Division of Genetic and Genomic Medicine. Fatty acid metabolism expert.
• George Gittes MD, Pitt Chair of Pediatric Surgery, Director of the Richard King Mellon Foundation Institute for Pediatric Research Pediatric Surgery. Pediatric surgeon and non-human primate expert.

Path to Impact Plan

Over the next 12 months the goal will be to generate strong preliminary data in a non-human primate preclinical model so this can then be submitted for a clinical trial at the conclusion of this study. Following this, we plan to evaluate the Tri-DC₈ in our various mouse models to determine the efficacy of this compound.

We plan on taking this from a provisional patent to the PCT stage (including formulation-based patent for Tri-DC₈) of the patent to commercially protect this intellectual property. Once adequately protected we will publish in a high impact journal, begin discussion with pharmaceutical companies and move towards a clinical trial. This therapy will affect many patients in all clinical settings and will greatly reduce the morbidity and mortality associated with AKI.

Frequently Asked Questions

• What is the impact beyond PInCh? Tri-DC₈ is a modified and novel DCA formulation. Tri-DC₈ will be a critical therapeutic not only in acute but also in chronic kidney disease, and kidney transplantation. Longer-chain DCAs like DC₁₀ and DC₁₂, are not kidney specific like DC₈ and will have many applications in liver and muscle.
• DCAs have been used in other settings, will this limit ability to patent? Around 20 years ago, DC₁₂ was proposed as a diabetes therapy, but this application was not successful. There are no active patents in the DCA space. DC₈, the kidney-specific chain length, has not been tested in other settings. Importantly, our recent production of a DCA-derived compound (triglyceride) will improve patentability.
• Is FDA approval required for DC8? Most likely yes, based on the recent approval of an odd-chain fatty acid (C7) in its triglyceride form (triheptanoin) like our Tri-DC₈, now marketed under name “Dojolvi.” Dojolvi was fast-tracked through the process.
• What is the timing of therapy use for patients? We have data that shows 24 hours of treatment is sufficient elicit the enhanced protein succinylation in kidney. We will continue to optimize this to determine whether this timing also leads to enhanced protection.