title: Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease.
abstract: Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients. Trial registration: ClinicalTrials.gov NCT01715480.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States of America.|Center for Genomic and Computational Biology, Duke University, Durham, NC, United States of America.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Doss
authors.affiliation: Division of Hematology, Department of Medicine, and Duke Comprehensive Sickle Cell Center, Duke University, Durham, NC, United States of America.
authors.forename: Jude C
authors.initials: JC
authors.lastname: Jonassaint
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC, United States of America.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Garrett
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC, United States of America.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Ashley-Koch
authors.affiliation: Division of Hematology, Department of Medicine, and Duke Comprehensive Sickle Cell Center, Duke University, Durham, NC, United States of America.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States of America.|Center for Genomic and Computational Biology, Duke University, Durham, NC, United States of America.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism; D001937:Brassica / Q000737:chemistry*; D002478:Cells, Cultured; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013454:Sulfoxides
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D013454:Sulfoxides; D051547:Heme Oxygenase-1; C016766:sulforaphane