double-blind placebo controlled study to evaluate the effect of nad+ boosting with nicotinamide riboside on immunometabolism and immunity in systemic lupus erythematosus

Conditions: Systemic Lupus Erythematosus (Sle)

Summary: study description: systemic lupus erythematosus (sle) occurs predominantly in women and is driven by type i interferon dysregulation and neutrophil hyperresponsiveness. neutrophils in females have reduced mitochondrial bioenergetic capacity which affects immunometabolism. nicotinamide adenine dinucleotide (nad)+ boosting with nicotinamide riboside blunts type 1 ifn activation in-vivo in monocytes of healthy subjects and ex-vivo in sle subjects. these findings support the proposal of the hypothesis that nad+ boosting by nr supplementation will modulate metabolic pathways in lupus and blunt type 1 interferon signaling. moreover, as type 1 interferon drives endothelial dysfunction, linked to increased cardiovascular risk, the effect of nr on endothelial function will be examined. objectives: primary objective: evaluate the effect of nr vs. placebo on immunometabolic and inflammatory remodeling in female sle subjects: exploratory objective: compare and characterize myeloid cell bioenergetic and immunometabolic profiles in healthy control and sle female subjects endpoints: primary endpoint: the primary end point will be to assess the effect of nr on blunting type i ifn signaling by measuring monocytic secretion of ifn-beta secretion compared to baseline in response to placebo vs. nr supplemented in sle study subjects. exploratory endpoints: healthy control vs. sle subjects: * compare type i ifn transcript profiles in monocytes and neutrophils at baseline and in response to activation. * assess cell bioenergetics including: 1) monocyte and neutrophil metabolic flux mass spectroscopy of 13c-glucose and 13cglutamine analysis to investigate their metabolic fates; (iii) mitochondrial oxygen consumption (using glucose, amino acid, and fatty acid substrates) and glycolysis rates. sle baseline vs. nr/placebo supplementation: baseline vs. 6 weeks of nr/placebo: -assess effect of nr on bioenergetics by measuring steady-state metabolite levels comparing changes in placebo vs. nr groups in monocytes and neutrophils. baseline vs. 12 weeks of nr/placebo: * whole blood nad+ levels (batched and measured at the end of study enrollment period) * explore effects of nr on gene regulation using monocyte and neutrophils by rna-seq and chromatin remodeling analysis. * determine the effect of nr vs placebo on endothelial dysfunction in sle subjects

study description: systemic lupus erythematosus (sle) occurs predominantly in women and is driven by type i interferon dysregulation and neutrophil hyper-responsiveness. neutrophils in females have reduced mitochondrial bioenergetic capacity which affects immunometabolism. nicotinamide adenine dinucleotide (nad)+ boosting with nicotinamide riboside blunts type 1 ifn activation in-vivo in monocytes of healthy subjects and ex-vivo in sle subjects. these findings support the proposal of the hypothesis that nad+ boosting by nr supplementation will modulate metabolic pathways in lupus and blunt type 1 interferon signaling. moreover, as type 1 interferon drives endothelial dysfunction, linked to increased cardiovascular risk, the effect of nr on endothelial function will be examined. objectives: primary objective: evaluate the effect of nr vs. placebo on immunometabolic and inflammatory remodeling in female sle subjects: exploratory objective: compare and characterize myeloid cell bioenergetic and immunometabolic profiles in healthy control and sle female subjects endpoints: primary endpoint: the primary end point will be to assess the effect of nr on blunting type i ifn signaling by measuring monocytic secretion of ifn-beta secretion compared to baseline in response to placebo vs. nr supplemented in sle study subjects. exploratory endpoints: healthy control vs. sle subjects: * compare type i ifn transcript profiles in monocytes and neutrophils at baseline and in response to activation. * assess cell bioenergetics including: 1) monocyte and neutrophil metabolic flux mass spectroscopy of 13c-glucose and 13c-glutamine analysis to investigate their metabolic fates; (iii) mitochondrial oxygen consumption (using glucose, amino acid, and fatty acid substrates) and glycolysis rates. sle baseline vs. nr/placebo supplementation: baseline vs. 6 weeks of nr/placebo: -assess effect of nr on bioenergetics by measuring steady-state metabolite levels comparing changes in placebo vs. nr groups in monocytes and neutrophils. baseline vs. 12 weeks of nr/placebo: * whole blood nad+ levels (batched and measured at the end of study enrollment period) * explore effects of nr on gene regulation using monocyte and neutrophils by rna-seq and chromatin remodeling analysis. * determine the effect of nr vs placebo on endothelial dysfunction in sle subjects

Eligibility criteria:
* inclusion criteria: in order to be eligible to participate in this study, an individual must meet all of the following criteria: sle subjects: * female subjects 18 years or older who meets \> 3 of 11 modified am. coll. of rheumatology (acr) (1997) revised criteria for sle and mild/moderate disease activity defined as an sle disease activity index 2000(sledai 2k) between zero and less than or equal to 14 at screening; * if on glucocorticoids, the dose must be less than or equal to 20 mg daily and stable for at least 4 weeks prior to screening; * if on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine, dose must have been stable for the 12 weeks prior to screening. the max. allowed doses - hydroxychloroquine 400 mg/day, chloroquine phosphate 500 mg/day and quinacrine 100 mg/day; * if on immunosuppressive drugs (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus); dose must have been stable for the 12 weeks prior to screening * subjects of childbearing potential must agree to practice effective birth control for the duration of the study; * stated willingness to comply with all study procedures and availability for the duration of the study; * agreement to adhere to lifestyle considerations throughout study duration; * ability of subject to understand and the willingness to sign a written informed consent document. * if on vitamin b3 or tryptophan supplementation at screening, willing to stop it at least 6 weeks before the baseline visit. control subjects: * female subjects 18 years or older * no history of autoimmune or inflammatory disease * if on vitamin b3 or tryptophan supplementation at screening, willing to stop it at least 6 weeks before the blood draw visit. exclusion criteria: sle subjects: * active renal or central nervous system disease or major renal or hepatic dysfunction; * treatment with rituximab, belimumab or any other biologic agent within the 6 months prior to screening * treatment with cyclophosphamide or ivig within the 6 months prior to screening and or increase in glucocorticoid dose within 4 weeks of screening; * pregnancy or lactation (nursing) * treatment with another investigational drug or other intervention within 6 months of screening control subjects: * inability to sign consent * pregnancy or nursing pregnant women are excluded from participation on this study. self-reported pregnancy status may be accepted from female control participants of child-bearing potential for a blood draw which is considered a minimal risk procedure.

Keywords: lupus chronic inflammation