A new review published in the Journal of the American Society of Nephrology (JASN) shows how stem cell based therapies in mice can slow down the progression of kidney disease in Alport Syndrome: “Stem Cell Therapies Benefit Alport Syndrome” LeBleu V et al, 2009.
These are exciting results for people affected by the syndrome but it’s findings have wider implications, as the authors state: “Our study opens up many considerations of how new therapies related to the use of stem cells can be devised for our kidney patients with chronic disease.” Crucially, because the mechanism of pathogenesis of this disease is comprehensively understood, devising effective therapies are the next strategic step.
Alport syndrome is a genetic kidney disease, most often occurring in males and is characterised by progressive kidney disease leading to kidney failure at a young age. Patients may also develop hearing loss and eye disease as well. Current treatment slows down the progression of kidney disease and there is currently no cure for Alport syndrome. Similarities of this disease to BHD syndrome exist in that a single gene defect effects three separate organs – the most serious of these being the kidney. Alport syndrome is caused by mutations in the genes COL4A3, COL4A4, and COL4A5. These are collagen biosynthesis genes and mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, an important structural component of basement membranes in the kidney, inner ear, and eye.
Collagen biosynthesis genes, or rather defective collagen biosynthesis genes, is a theme that repeats itself in another genetic syndrome that bears similarities to BHD Syndrome. Obviously in this example they cause Alport syndrome due to defective basement membrane composition but in VHL disease, mutant VHL protein has been shown to fail to interact with COL4A2, correlating to a loss of collagen IV network formation in vitro and collagen IV remodelling in vivo (Kurban G et al, 2008). Also a rare disease called Ehlers-Danlos syndrome results in epidermal lesions (as well as joint hyperlaxity) and is caused by defects in COL5A1 and COL5A2, resulting in irregular composition of collagen fibers (Symoens S et al, 2009).
Given that the remit of this blog is to spark new ideas and think outside the box, I could speculate that this early line of evidence could suggest that the varied and disparate organs affected in BHD could be caused by errors in cell-cell contact mechanisms caused by deficiencies in the extracellular matrix and collagen network. Food for thought indeed!