Stem Cell Therapies Benefit Alport Syndrome

Abstract

Patients with Alport syndrome progressively lose renal function as a result of defective type IV collagen in their glomerular basement membrane. In mice lacking the ␣3 chain of type IV collagen (Col4A3 knockout mice), a model for Alport syndrome, transplantation of wild-type bone marrow repairs the renal disease. It is unknown whether cell-based therapies that do not require transplantation have similar potential. Here, infusion of wild-type bone marrow-derived cells into unconditioned, nonirradiated Col4A3 knockout mice during the late stage of disease significantly improved renal histology and function. Furthermore, transfusion of unfractionated wild-type blood into unconditioned, nonirradiated Col4A3 knockout mice improved the renal phenotype and significantly improved survival. Injection of mouse and human embryonic stem cells into Col4A3 knockout mice produced similar results. Regardless of treatment modality, the improvement in the architecture of the glomerular basement membrane is associated with de novo expression of the ␣3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.

Feasibility of Repairing Glomerular Basement Membrane Defects in Alport Syndrome

“…These include efforts to prevent the development of GBM lesions and glomerulosclerosis [13][14][15] ; to attenuate the glomerular and tubulointerstitial inflammation that inevitably occurs [16][17][18] ; and to transplant or infuse various types of stem cells, with or without irradiation, with the goal of replacing mutant podocytes with exogenous cells capable of expressing the missing collagen a3a4a5(IV). [19][20][21][22] Despite claims of success at replacing podocytes and/or restoring GBM composition, [19][20][21] these results stirred controversy 23 and have not been convincingly replicated. The recent finding that injection of amniotic fluid stem cells is beneficial in Alport mice without any effect on GBM composition or glomerular cell identity 24 suggests that exogenous cells do not need to home to glomeruli, cross the GBM, and replace or fuse with mutant podocytes (if such events are even possible) to be ameliorative.…”

Long-term management of Alport syndrome in pediatric patients

“…In theory, any child with Alport syndrome anywhere in the world should be able to receive treatment with an ACE inhibitor. This cannot be said for certain other treatments, for example, stem cell therapy that have shown promise in murine Alport syndrome, [20][21][22][23][24] or for novel proprietary agents. At the present time, our ability to assess the effect of angiotensin inhibition (or any other therapy) on progression of Alport nephropathy in individual patients is limited.…”

Induced Pluripotent Stem Cells from Human Kidney

“…16 Although both embryonic and adult stem cells have the potential to differentiate into every cell type of the body, in the vast majority of studies, the efficiency is low and differentiation is sporadic. Therefore, with notable exceptions, 17 the road to clinical application of native stem cell-based therapy for kidney has been uncertain.…”