Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches.
Mevalonate kinase deficiency (MKD) is a rare inborn auto-inflammatory disease due to the impairment of the pathway for the biosynthesis of cholesterol and non-sterol isoprenoids. The shortage of isoprenoids compounds and in particular of geranylgeranylpyrophosphate (GGPP) was recently associated to the MKD characteristic inflammatory attacks. The aim of this study is to demonstrate that the normalization of the mevalonate pathway intermediates levels and in particular of GGPP, through the specific inhibition of farnesyl-transferase (FT) with Manumycin A could ameliorate the inflammatory phenotype of MKD patients. The effect of Manumycin A was first evaluated in MKD mouse and cellular models, chemically obtained using the aminobisphosphonate alendronate (ALD), and then in monocytes isolated from 2 MKD patients. Our findings were compared to those obtained by using natural exogenous isoprenoids (NEIs). Manumycin A was able to significantly reduce the inflammatory marker serum amyloid A in ALD-treated Balb/c mice, as well as IL-1 beta secretion in ALD-monocytes and in MKD patients. These results clearly showed that, through the inhibition of FT, an increased number of mevalonate pathway intermediates could be redirected towards the synthesis of GGPP diminishing the inflammatory response. The importance in limiting the shortage of GGPP was emphasized by the anti-inflammatory effect of NEIs that, due to their biochemical structure, can enter the MKD pathway. In conclusion, manumycin A, as well as NEIs, showed anti-inflammatory effect in MKD models and especially in MKD-monocytes, suggesting novel approaches in the treatment of MKD, an orphan disease without any efficacious treatment currently available.
De Leo
Luigina
L
Department of Reproductive and Developmental Sciences, and Public Healthcare, University of Trieste, Italy.
Marcuzzi
Annalisa
A
Decorti
Giuliana
G
Tommasini
Alberto
A
Crovella
Sergio
S
Pontillo
Alessandra
A
D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D054078:Mevalonate Kinase Deficiency / Q000188:drug therapy* / Q000276:immunology; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011090:Polyenes / Q000627:therapeutic use*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000627:therapeutic use*; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D011090:Polyenes; D011106:Polyisoprenyl Phosphates; D053284:Polyunsaturated Alkamides; D051231:Farnesyltranstransferase; C002963:geranylgeranyl pyrophosphate; C054474:manumycin; D008798:Mevalonic Acid