Researchers Identify Potential Treatment For Deadly Kidney Disease

By C. Rajan, contributing writer

Biochemists at UCLA have uncovered a potential treatment for PH1, a rare and potentially deadly genetic kidney disease in children.

The researchers found that when a key enzyme went to the wrong location or “address” within a cell, it led to disease. They were able to identify a compound which could help direct the enzyme to the correct location instead. Their findings may also help with developing treatments for other diseases such as Parkinson's and Alzheimer's disease.

PH1 (primary hyperoxaluria 1) is a disease that starts at birth and causes kidney failure by age 15 in over half of those with the disease. The disease is fatal for patients unless they receive both kidney and liver transplants.

In normal persons, the key metabolic enzyme alanine glyoxylate aminotransferase (AGT) is supposed to go to a location inside the cell called the peroxisome. However, in people with PH1, there is a certain genetic mutation which causes the AGT enzyme to go instead to the cell’s mitochondria, leading to the disease.

The research team identified a compound called dequalinium chloride, or DECA, that can prevent AGT enzyme from going to the wrong location within a cell. By ensuring that AGT goes to the proper ‘address’ in the cell, PH1 and possibly other such diseases, can be prevented.

DECA is a FDA-approved anti-bacterial and anti-fungal agent that is the active ingredient in several medications. When the researchers added small amounts of DECA to cells in a Petri dish, AGT was prevented from going to the mitochondria and sent to its proper location, the peroxisome.

"In many mutations that cause diseases, the enzyme doesn't work," said Dr. Carla Koehler, lead investigator and a professor of chemistry and biochemistry at UCLA. "In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria 'mailbox' and takes it to the peroxisome address instead."

In persons carrying the PH1 mutation, the AGT does contain the correct peroxisome address, but the cells ignore it as they read the accompanying address of the mitochondria first, Dr. Koehler said.

Dr. Koehler is now investigating whether a similar ‘correct address’ strategy can fight cancer. Her team has already identified approximately 100 other small molecules which are now being tested for their ability to combat Parkinson's, Alzheimer's, and other diseases.

The study was published online in the Proceedings of the National Academy of Sciences.