Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency

Abstract Objective In cells from patients with the autoinflammatory disorder mevalonate kinase (MK) deficiency, which includes the hyperimmunoglobulin D with periodic fever syndrome, MK becomes the rate‐limiting enzyme in the isoprenoid biosynthesis pathway. This suggests that up‐regulation of residual MK activity in these patients could be a way in which to prevent or alleviate the associated symptoms. We studied the effect of 2 specific inhibitors of isoprenoid biosynthetic enzymes on the residual activity of MK in cells from patients with MK deficiency. Methods Skin fibroblasts from MK‐deficient patients and from controls were cultured for 7 days with either simvastatin, an inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, or zaragozic acid A, an inhibitor of squalene synthase. Following culture, MK activity, MK protein levels, MVK messenger RNA levels, and the effect on the pathway flux toward nonsterol isoprenoid biosynthesis were determined. Results Treatment of the fibroblasts with either of the inhibitors led to a marked increase in residual MK enzyme activity, which was largely attributable to increased MVK gene transcription. This effect was even more pronounced when the cells were cultured in lipoprotein‐depleted medium. The flux toward nonsterol isoprenoid end‐product synthesis was reduced when cells were treated with simvastatin but was partly restored by concomitant treatment with zaragozic acid A. Conclusion Our results indicate that manipulations of the isoprenoid biosynthesis pathway that promote the synthesis of nonsterol isoprenoids may provide an interesting therapeutic option for the treatment of MK deficiency.