A drug previously developed at UCLA to help heart tissue repair itself after a heart attack may also help repair and regenerate kidney tissue, researchers have found.
The drug, called AD-NP1, which was recently approved by the FDA for a Phase 1 clinical trial in humans, works on heart tissue by blocking a protein that disrupts healing and prevents internal organs from fully recovering. Researchers have now found that blocking this protein in kidney tissue speeds up recovery after kidney injury in mice.
The new finding, published in Cell stem cellis based on years of research in the laboratory of UCLA cardiovascular scientist Arjun Deb.
His team discovered that an injured kidney produces a protein called ENPP1 that starts a metabolic chain of events, shutting down the energy production and function of multiple cells in the injured area, preventing tissue repair. The researchers found that blocking ENPP1 enhanced kidney repair and reduced scar tissue formation, thereby improving kidney function. Deb’s team previously determined that blocking ENPP1 in heart tissue improved healing.
Deb’s team looked at kidney biopsies from people with chronic kidney disease and found that ENPP1 was expressed at higher levels than in healthy tissue. They then fed mice a kidney-toxic diet and administered drugs that cause kidney damage to normal mice and mice with genes blocked for ENPP1 production. Blood tests showed that all of these mice had significant increases in serum creatinine, BUN, and cystatin C, which are signs of kidney dysfunction. But after four weeks, these levels were significantly reduced in mice that could not produce ENPP1 compared to control mice, indicating that their kidneys were healing.
Having confirmed that blocking the ENPP1-mediated metabolic cascade improved kidney repair, the researchers induced kidney damage in normal mice and administered their drug, AD-NP1. Just seven days later, the mice showed improved kidney function, and follow-up inspection of their kidneys revealed less scarring.
These animals had a much better outcome. Their kidneys were not as damaged and the kidney cells proliferated more. We found that the same mechanisms we observed in the heart were applicable to the kidney. After injury, the healthy cells around the damaged area tried to proliferate, but the damaged area sent metabolic signals that prevented the kidney from effectively regenerating and repairing itself.”
Arjun Deb, professor of medicine and molecular, cell and developmental biology at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
AD-NP1, which Deb’s team developed entirely at UCLA with public funding, is a monoclonal antibody engineered in the lab to mimic the function of natural antibodies produced by our immune system. Just as our immune system can produce specific antibodies to bind and inactivate specific pathogens, AD-NP1 monoclonal antibody has been engineered to target human ENPP1 and no other human protein.
The drug was approved for Phase 1 human clinical trials in September for the heart. Phase 1 trials evaluate the safety, dosage and metabolism of new drugs and are the first step towards trials evaluating their effectiveness. Deb plans to apply for kidney tests as well.
The research was funded by the National Institutes of Health, the California Institute for Regenerative Medicine and the Department of Defense.
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