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Geranylgeraniol supplementation leads to an improvement in inflammatory parameters and reversal of the disease specific protein signature in patients with hyper-IgD syndrome

Sediva, A.; Orlicky, M.; Vrabcova, P.; Klocperk, A.; Kalina, T.; Fujiwara, H.; Hsu, F.-F.; Bambouskova, M.

2024-07-18 allergy and immunology
10.1101/2024.07.17.24309492 medRxiv
Show abstract

Mevalonate kinase (MVK) deficiency, a rare autosomal recessive disease, significantly impacts metabolism and immunity, leading to mevalonic aciduria in severe cases and hyper-IgD syndrome (HIDS) in partial deficiency. These conditions arise due to disruptions in the mevalonate pathway, which is essential metabolic pathway responsible for the synthesis of non-sterol isoprenoids and other molecules. The resulting metabolic blockade triggers autoinflammatory responses, primarily due to deficient isoprenoid intermediates such as geranylgeranyl pyrophosphate (GGPP). This first reported pilot study evaluates the safety and efficacy of dietary geranylgeraniol supplementation (GG) in three patients with HIDS. Over three months, GG supplementation showed no liver toxicity and did not alter lipid profiles. Although GG did not rise the plasma levels of GGPP, the plasma proteomics showed significant changes induced by GG. Proteomic analysis further revealed that GG supplementation can reverse some of the features of HIDS-specific plasma protein signature, highlighting its potential to modulate inflammation and protein prenylation pathways. These findings suggest that GG supplementation could be a promising metabolic intervention to mitigate inflammation in HIDS, warranting further, more targeted investigation in larger clinical trials.

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