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Alport Syndrome Treatment

Alport Syndrome Treatment

The rate of progression of Alport syndrome is variable. The aim of the Alport Syndrome Research Program is to slow or halt disease progression entirely.

The programs subprojects are as follows:

(1) Regulation of the developmental shift from type IV α-1,2 to α-3,4,5 collagen.

Type IV α-1,2 collagen basement membranes support renal function in fetal development and early life. If the switch to α-3,4,5 collagen membranes could be controlled, this may be a novel treatment for kidney, ear and eye manifestations of Alport syndrome. NIT's access to renal tissue through collaboration and expertise in gene expression studies have set the stage for this subproject.

(2) Podocyte interaction with kidney basement membrane

Podocytes produce type IV collagen then interact with it to perform the filtration function of the kidney. For some unknown reason, adult podocytes fail to function properly on α-1,2 collagen and the other molecules associated with glomerular basement membranes. To achieve normal function of podocytes in Alport kidneys, the interaction between GBM containing α-1,2 and α-3,4,5 collagens must be understood.

(3) Podocyte distress signals in Alport kidneys

Adult podocytes that fail to interact and function with α-1,2 collagen GBM produce soluble factors that constitute ‘distress signals’. It is anticipated that these signals are chemokines, but a whole genome screen to compare genes differentially expressed in adult podocytes cultured on α-1,2 or α-3,4,5 collagen matrices would provide a definitive answer and potentially identify a therapeutic target.

Alport Program Schematic

(4) Interstitial fibrosis

Interstitial fibrosis is the common final pathway of end-stage renal disease, triggered by a variety of stimuli. After transplantation, this mechanism is part of the process of ‘chronic rejection’. In the latter case, interstitial fibrosis is triggered by inflammation and the release of fibrotic mediators, especially TGF-β. The same mediators have been identified in Alport kidneys.

    • Part (a) of this project studies profibrotic (scar-inducing) properties of podocyte ‘distress signals’ (see above). This may identify a therapeutic target.
    • Part (b) will be a study of the background gene profiles associated with the rate of progression to fibrosis in Alport patients. It is known in other diseases, for example cystic fibrosis, that genetic background plays a big role in survival. This study may identify target genes for therapeutic intervention in Alport syndrome.
    • Part (c) will be a clinical trial of ACE inhibitors and statins in children with Alport disease. These agents are widely used in adult renal disease, but their efficacy and safety has never been proven in children. 

(5) Stem cell therapy
Stem cells derived from bone marrow or amniotic fluid differentiate into podocytes. The ‘distress signals’ from Alport podocytes seem to transmit the homing and differentiation information. Hence, stem cell transfer presents a potential therapeutic intervention.

Cure of Alport Syndrome
Since Alport syndrome is a consequence of mutations in type IV collagen genes, a cure may be effected by replacement of the defective genes or by supplying the gene product (namely type IV collagen).To date, gene therapy in models of Alport syndrome, as in other diseases, has been a disappointing failure. In Alport syndrome, getting enough copies of the normal collagen genes into the right place in the kidney has proved to be exceedingly difficult. New gene vectors are now becoming available, but their efficacy and safety have yet to be established. *[1] Delivery of proteins into the kidney may be more problematic than gene therapy, especially because of the configurational constraints in forming new basement membranes within the kidney glomeruli.  

[1] Karl Tryggvason, Billy Hudson, George Lees and Bogdan Borza are leading the project.



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