Taken together with the CD68 data, these results suggest that systemic treatment of the K14 mouse with GZ 161 results in decreased numbers of macrophages/microglia in multiple brain regions. Whether these decreases are stable relative to vehicle treated K14 mice or simply indicate a delay in the accumulation of these cells in the brain is not clear. The intravenous use of commercial forms of recombinant human glucocerebrosidase is regarded as the gold standard for the treatment of Gaucher disease, and provides significant improvement in the hematological, skeletal, visceral and quality of life outcomes of patients ; substrate inhibition approaches are also included in the therapeutic modalities available for Gaucher disease and have lately shown promising results. Current experience using high doses of rhGC for treating neuropathic Gaucher disease has yielded mixed results, and has not confirmed the avoidance or stabilization of the neuropathic features of the disease in type 3 Gaucher disease patients. As one potential therapeutic approach, we have shown recently that direct ICV administration of rhGC to the lateral ventricles of a mouse model of type 2 nGD, namely the K14 mouse, facilitates the clearance of glycosphingolipid substrates and improves median lifespan. The identification of GZ 161 as a GCS inhibitor that can cross the BBB prompted us to evaluate this molecule in this same mouse model as a potential alternative or adjunct to other therapeutic approaches, such as ICV delivery of GC. Here we show both qualitatively and quantitatively that systemic administration of GZ 161 to neonatal K14 mice significantly reduces substrate load, D-AP4 ameliorates the pathological features of the disease and D-CPP-ene increases median lifespan. When combined with ICV-delivered rhGC, systemic administration of GZ 161 resulted in additive increases in lifespan, implying that such a combination might be more efficacious than either monotherapy alone in nGD patients. Given the implications of these studies that GZ 161 can apparently cross the BBB and inhibit its target enzyme, glucosylceramide synthase, it is reasonable to assume that this molecule could also be used to treat other LSDs resulting from a buildup of substrates downstream from GluCer. It is important to note that in the current studies, GZ 161 was administered to K14 mice in a time frame in which GluCer and GluSph were being produced in the developing mouse brain at relatively high rates compared to WT mice. Daily IP treatment with GZ 161 successfully reduced, but did not normalize GluCer and GluSph levels in the K14 brain. There are several lines of evidence suggesting that GluSph and other lysosphingolipids such as galactosylsphingosine may contribute to CNS pathology by initiating the production of inflammatory mediators.