Anti-IL11 therapies demonstrate beneficial effects in reducing the severity of disease in mice models of Alport syndrome.
Affecting about one in every 50,000 newborns globally, Alport syndrome is a genetic condition characterised by mutations that lead to abnormal collagen formation in certain tissues, which can result in eye abnormalities, hearing loss, and kidney disease. Due to damage and scar tissue formation in the glomerulus, which is responsible for removing toxins while retaining key proteins, people with Alport syndrome may experience progressive loss of kidney function and eventually, chronic kidney failure.
While there is currently no cure for this condition, clinicians have attempted to reduce the rate of kidney damage using angiotensin-converting enzyme inhibitors (ACEi). These drugs lower blood pressure and reduce leakage of protein into the urine. Unfortunately, many individuals with Alport Syndrome continue to progress to end-stage kidney failure despite treatment with ACEi.
Recently, scientists at Duke-NUS Medical School, Singapore, have developed a new treatment strategy that uses an antibody that inhibits a cell signalling protein called interleukin-11 (IL11). Although IL11 has been implicated in fibrotic kidney disease, its role in Alport syndrome remained elusive.
“Together with our collaborators in Singapore and Germany, we wanted to find out if IL-11 played a role in Alport syndrome disease development. This cell signalling protein had recently been implicated by other research in kidney scarring and dysfunction,” said lead author of the study, Dr. Anissa Widjaja, an assistant professor with Duke-NUS’ Cardiovascular & Metabolic Disorders (CVMD) Programme.
Using a mouse model of Alport syndrome in humans, the researchers discovered that IL11 levels began to rise in the test animals by six weeks of age. This resulted in damage to glomerular cells that make up the filtering sieve lying between the incoming blood and the outgoing urine.
“We also found that administration of anti-IL11 therapies, in the form of an antibody drug, has beneficial effects in reducing the severity of Alport syndrome in the mice,” explained Dr. Widjaja and Professor Stuart Cook. “This happened by reducing kidney injury, inflammation and scarring. Importantly, combining ACEi and anti-IL11 therapies increased the lifespan of Alport syndrome mice by more than 400 per cent relative to those that were treated with an ACEi drug alone.”
Given these findings, Dr. Widjaja and colleagues will continue their investigations to determine whether anti-IL11 therapies can reverse kidney failure by promoting tissue regeneration.
“This discovery spells new hope for treatment in Alport syndrome—not just to arrest the progress of the disease, but even to restore lost kidney function. Also, the study suggests that anti-IL11 therapeutics can have additive effects with ACEi treatment, enhancing its potential utility in the clinical arena,” commented Professor Thomas Coffman, Dean of Duke-NUS Medical School and a senior co-author of the study.
Source: Widjaja et al. (2022). A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome. Journal of the American Society of Nephrology, ASN.2021040577.