Immunosuppressant drug halts kidney cyst formation
Researchers from UC Santa Barbara and Hopkins have shown that an immunosuppressant drug called rapamycin could be effective against polycystic kidney disease (PKD).
PKD affects 12.5 million people around the world and is one of the most prevalent genetically inherited diseases. Over the patient's lifetime, multiple fluid-filled cysts form in the kidneys, replacing the healthy tissue and greatly enlarging the kidneys.
Complications include infected or ruptured cysts, urinary tract infections, liver failure and damage to other organs. About half of patients with autosomal dominant (AD) PKD experience kidney failure before the age of 50. There is currently no way to halt the formation of cysts.
Previous research done at UC Santa Barbara had shown that a molecular pathway called mTOR is fairly inactive in healthy kidney cells, but highly active in cells that surround the cysts of patients with PKD. They then showed that the drug rapamycin, known to inhibit the mTOR pathway and currently used as an immunosuppressant during kidney transplants, halted cyst formation.
However, this research was done in mice where the mTOR pathway was not activated in the same way as it is in humans with the disease. The mouse model had genetic mutations that led to mTOR activation and PKD, but these mutations were not in the Pkd1 or Pkd2 genes, which lead to the onset of the disease in humans. The scientists were not sure if their results with rapamycin would translate to humans.
Scientists working at Hopkins then developed a new mouse model with a mutation in the Pkd1 gene. The researchers were able to produce results with rapamycin in this new model that more closely resembled what happens in humans.
"We have now established that the kidney cysts caused by inactivation of Pkd1, the same gene affected in human ADPKD patients, correlates with activation of the mTOR pathway," Jonathan Shillingford, a project scientist at UCSB and lead author of the paper, said. "Taken together, our data demonstrate that rapamycin treatment is effective in a mouse model of Pkd that resembles the human disease process."
PKD affects 12.5 million people around the world and is one of the most prevalent genetically inherited diseases. Over the patient's lifetime, multiple fluid-filled cysts form in the kidneys, replacing the healthy tissue and greatly enlarging the kidneys.
Complications include infected or ruptured cysts, urinary tract infections, liver failure and damage to other organs. About half of patients with autosomal dominant (AD) PKD experience kidney failure before the age of 50. There is currently no way to halt the formation of cysts.
Previous research done at UC Santa Barbara had shown that a molecular pathway called mTOR is fairly inactive in healthy kidney cells, but highly active in cells that surround the cysts of patients with PKD. They then showed that the drug rapamycin, known to inhibit the mTOR pathway and currently used as an immunosuppressant during kidney transplants, halted cyst formation.
However, this research was done in mice where the mTOR pathway was not activated in the same way as it is in humans with the disease. The mouse model had genetic mutations that led to mTOR activation and PKD, but these mutations were not in the Pkd1 or Pkd2 genes, which lead to the onset of the disease in humans. The scientists were not sure if their results with rapamycin would translate to humans.
Scientists working at Hopkins then developed a new mouse model with a mutation in the Pkd1 gene. The researchers were able to produce results with rapamycin in this new model that more closely resembled what happens in humans.
"We have now established that the kidney cysts caused by inactivation of Pkd1, the same gene affected in human ADPKD patients, correlates with activation of the mTOR pathway," Jonathan Shillingford, a project scientist at UCSB and lead author of the paper, said. "Taken together, our data demonstrate that rapamycin treatment is effective in a mouse model of Pkd that resembles the human disease process."
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Adriana Castillo
posted 2/05/10 @ 11:56 PM EST
I would like to receive follow up information regarding this potential treatment for people with PKD.
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