Small Molecule AC1903 Stops the Progression of Kidney Disease in Animal Models

Small Molecule AC1903 Stops the Progression of Kidney Disease in Animal Models

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Highlights:
  • Researchers from the Broad Institute, MIT and Harvard, Brigham and Women's Hospital and Harvard Medical School haves identified a small molecule which stops the progression of kidney disease
  • Kidney damage is usually caused by destruction of cells responsible for the filtering process. These cells known as podocytes filter toxins and keep proteins out of blood
  • In the mouse model, AC1903 protected the podocytes, controlled proteinuria and restored kidney function.
Small Molecule AC1903 Stops the Progression of Kidney Disease in Animal Models
A research team from the Broad Institute, MIT and Harvard, Brigham and Women's Hospital and Harvard Medical School has identified a small molecule which stops the progression of kidney disease.
Small Molecule AC1903 Stops the Progression of Kidney Disease in Animal Models

Treatment options for chronic kidney disease have been limited so far. The last 40 years have not seen any progress in drug development and even patients who receive a transplant ultimately succumb to dialysis and death.

A research team from the Broad Institute, MIT and Harvard, Brigham and Women's Hospital and Harvard Medical School has identified a small molecule which stops the progression of kidney disease.

Senior author Anna Greka (member of the Broad Institute, associate physician at Brigham and Women's Hospital and assistant professor at Harvard Medical School) and her colleagues started their research on the rare genetic kidney disease FSGS using a mouse model to understand the genes involved, proteins and molecular pathways occurring in kidney damage and deterioration. In FSGS, scarring of the glomeruli is usually caused by destruction of cells responsible for the filtering process. These cells known as podocytes filter toxins and keep proteins out of blood. Destruction of podocytes leads to protein leak into the kidneys and into the urine. This condition known as proteinuria is majorly responsible for destroying the kidneys.

In FSGS, the investigators knew that a genetic mutation activates a protein called Rac1 which in turn activates another protein TRPC5 which causes excess calcium flow into the podocytes thereby destroying it. According to Greka, the team was focused on trying to find a drug which prevents destruction and damage of podocytes and protects kidney function. The team believes that this therapeutic research is not just beneficial for FSGS but all patients with chronic kidney disease since the group of kidney disorders have a shared pathway for kidney failure.

The researchers designed and tested several compounds before zeroing in on AC1903 which was able to block this process of podocyte destruction. AC1903 has been named after Anna Greka and co-author Corey Hopkins (University of Nebraska Medical Center College of Pharmacy). In the mouse model, AC1903 protected the podocytes, controlled proteinuria and restored kidney function. Even in advanced kidney disease, the compound was able to prevent loss of podocytes and protect kidney function.

The team also successfully tested AC1903 in mouse models with hypertension where the kidney function again improved. The research indicated that TRPC5 mechanism which causes damage to podocytes has a role in other kidney diseases too apart from FSGS. While in FSGS, damage was due to a genetic mutation; factors like high blood pressure was the trigger in other chronic kidney diseases. The team believes that TRPC5 inhibitors have a broad role in a range of kidney disorders.

The research is very encouraging for 10% of the world's population is affected with chronic kidney disease. The 2010 Global Burden of Disease study found that chronic kidney disease ranks 18 in the cause for worldwide deaths and over 2 million people worldwide either receives dialysis regularly or a kidney transplant. The discovery of the new molecular compound AC1903 brings hope to the millions of sufferers globally. This exciting research now awaits human clinical studies.

What is progressive kidney disease?

Progressive kidney diseases are caused by damage to the kidney's filtration process. The Glomerular Filtration Rate (GFR) is usually damaged in kidney conditions. The GFR is the rate at which the kidneys filter the waste and also relate to measuring kidney function. In chronic kidney disorders, GFR rate slowly comes down leading to renal insufficiency and ultimately renal failure and death.

One of the rare genetic kidney diseases is a condition known as Focal Segmental Glomerulosclerosis (FSGS) which attacks the kidney's filtering units, glomeruli. This leads to scarring of the kidneys and ultimately kidney failure. FSGS has a range of symptoms which include proteinuria where protein leaks into the kidneys and urine, edema or swelling in the legs, feet and face, high cholesterol and high blood pressure. FSGS is caused by a rare genetic mutation, side effects of other blood disorders like sickle cell anemia and other autoimmune disorders.

Currently, there are no targeted drugs for chronic kidney diseases or FSGS. The only treatment modalities include diuretics and low-sodium diet; ACE-inhibitors to control blood pressure and reduce proteinuria, anticoagulants to stem blood clots and statins to lower blood cholesterol. People with chronic kidney disorders ultimately need dialysis and transplants.

References:
  1. Zhou, Greka, Castonguay, Sidhom et al. (2017) "A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models." Science 358(6368), pp. 1332-1336. DOI: 10.1126/science.aal4178
  2. Ericson, A., and B. Källén. "Congenital malformations in infants born after IVF: a population-based study." Human reproduction 16, no. 3 (2001): 504-509. https://doi.org/10.1093/humrep/16.3.504
  3. Kidney Internation - (https://nephcure.org/)
  4. Chronic Kidney Disease Stages - (http://www.nationalkidneycenter.org/chronic-kidney-disease/stages/)
  5. Global Facts: About Kidney Disease - (https://www.kidney.org/kidneydisease/global-facts-about-kidney-disease)

Source: Medindia

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