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Using these three mouse models, the authors showed dose-dependent improvements of symptoms with Genz-123346, a specific inhibitor of the synthesis of GlcCer4 (Fig. 1). These improvements were documented both histo-logically and functionally as decreases in kidney weight relative to body weight, reduced cystic volume and decreases in blood urea nitrogen. Pcy mice, which develop fibrosis coincident with cystogenesis, also showed reduced fibrosis after receiving Genz-123346. In the mouse model of ADPKD, the authors found that Genz-123346 improved indices of cyst formation and renal function4.
The normal growth and differentiation of kidney cells requires a tightly regulated balance between proliferation and apoptosis. Studies have shown that both pathways are disrupted in PKD. Natoli et al.4 found that acute treatment with Genz-123346 inhibited the Aktmammalian target of rapamycin proliferation pathway, one of the pathways known to be turned on in PKD, without any changes in apoptosis. In contrast, chronic treatment with the inhibitor reduced both proliferation and apoptosis.
Collectively, these findings provide preclinical validation for a small-molecule inhibitor of GlcCer synthesis that may have a positive effect on disease pathogenesis. But they also raise two sets of interesting questions.
The first question has to do with how easy it will be to develop Genz-123346 into a drug with clinical utility in the setting of PKD. Like cancer chemotherapeutics, Genz-123346
exerts antiproliferative effects on cells. If patients with PKD require chronic treatment with this inhibitor, then researchers will need to first identify the effects of blocking sphingolipid synthesis, both acutely and chronically, on various organ systems. This issue is especially relevant in PKD, as most rodent models of the disease, in which potential therapies are initially evaluated, have an aggressive condition that progresses rapidly, whereas the human condition develops much more slowly and over longer periods of time. Thus, humans with PKD may require sustained drug treatment, substantially increasing the potential risks of long-term side effects from an anti-proliferative drug.
The second and, from a biological perspective, more interesting set of questions asks what the importance is of elevated glycosphingolipid levels in PKD. What processes lead to their production, and how are these processes affected by mutations in the genes that cause PKD? Do glycosphingolipids themselves...