Background: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare
autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the
enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate-
derived intermediates, which results in unbalanced prenylation of proteins and altered
metabolism of sterols. These defects lead to a complex multisystem inflammatory and
Objective: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin-
1 can significantly reduce inflammation, they cannot completely control the clinical
symptoms that affect the nervous system. For this reason, MKD can still be considered an
orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation,
is crucial to improve the knowledge on its pathogenesis, which is still unknown.
New therapies are also required in order to improve pateints’ conditions and their
quality of life.
Methods: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived
isoprenoids. Of note, these cells present an exaggerated response to inflammatory
stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase,
thus increasing the availability of isoprenoids intermediates upstream the enzymatic
Results: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a
drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago,
with a good safety profile.
Conclusions: Here we describe the preclinical evidence supporting the possible repositioning
of TAK-475 from its originally intended use to the treatment of MKD and discuss its
potential to modulate the mevalonate pathway in inflammatory diseases.