Featured Publications
A dual-acting DNASE1/DNASE1L3 biologic prevents autoimmunity and death in genetic and induced lupus models
Stabach P, Sims D, Gomez-Bañuelos E, Zehentmeier S, Dammen-Brower K, Bernhisel A, Kujawski S, Lopez S, Petri M, Goldman D, Lester E, Le Q, Ishaq T, Kim H, Srivastava S, Kumar D, Pereira J, Yarema K, Koumpouras F, Andrade F, Braddock D. A dual-acting DNASE1/DNASE1L3 biologic prevents autoimmunity and death in genetic and induced lupus models. JCI Insight 2024, 9 PMID: 38888971, DOI: 10.1172/jci.insight.177003.Peer-Reviewed Original ResearchSystemic lupus erythematosusDNASE1L3 deficiencySporadic systemic lupus erythematosusAssociated with systemic lupus erythematosusChromatin degradationDNA accumulationDevelopment of lupusPristane-induced lupusSelf-DNACell free DNAHuman isoformsSystemic lupus erythematosus plasmasDouble knockout miceDNASE1L3Pathogenic effectsFree DNALupus modelEnzymeInducible lupus modelAdult patientsLupus erythematosusKnockout micePediatric populationAutoimmune diseasesDNA
2024
Quantitative correlation of ENPP1 pathogenic variants with disease phenotype
Ansh A, Stabach P, Ciccone C, Cao W, De La Cruz E, Sabbagh Y, Carpenter T, Ferreira C, Braddock D. Quantitative correlation of ENPP1 pathogenic variants with disease phenotype. Bone 2024, 186: 117136. PMID: 38806089, PMCID: PMC11227391, DOI: 10.1016/j.bone.2024.117136.Peer-Reviewed Original ResearchEctonucleotide pyrophosphatase/phosphodiesterase 1Pathogenic variantsDisease phenotypeEnzyme velocityCompound heterozygotesEnzyme activityVariable enzyme activityAutosomal dominant phenotypeHigh-throughput assayAutosomal recessive formInnate immune responseENPP1 variantsDamaging variantsENPP1 deficiencyCole diseaseDominant phenotypeAutosomal dominant diseaseCatalytic velocityRecessive formEnzymePhenotypeWT levelsBio-active moleculesClinical phenotypeDominant disease
2022
Outer hair cell function is normal in βV spectrin knockout mice
Stankewich MC, Bai JP, Stabach PR, Khan S, Tan WJT, Surguchev A, Song L, Morrow JS, Santos-Sacchi J, Navaratnam DS. Outer hair cell function is normal in βV spectrin knockout mice. Hearing Research 2022, 423: 108564. PMID: 35864018, DOI: 10.1016/j.heares.2022.108564.Peer-Reviewed Original ResearchConceptsOuter hair cellsAuditory brainstem response wavesAuditory thresholdOuter hair cell functionSpiral ganglion neuronsEfferent nerve fibersHair cell functionNumber of afferentsGanglion neuronsNerve fibersKnockout miceNeuronal structuresMiceHair cellsCell functionElectromechanical activityPutative roleType IOngoing investigationExon deletionsSynaptopathyAfferentsData supportResponse wavesNeuronsResponse of enthesopathy in ENPP1 deficiency to enzyme replacement therapy in murine models and enthesopathy comorbidities and quality of life in ENPP1‐deficient adults
Ansh A, Nester C, O'Brien C, Stabach P, Murtada S, Lester E, Khursigara G, Molloy L, Carpenter T, Ferreira C, Braddock D. Response of enthesopathy in ENPP1 deficiency to enzyme replacement therapy in murine models and enthesopathy comorbidities and quality of life in ENPP1‐deficient adults. The FASEB Journal 2022, 36 DOI: 10.1096/fasebj.2022.36.s1.r5311.Peer-Reviewed Original ResearchENPP1 deficiencyQuality of lifeMusculoskeletal complicationsReplacement therapyBrief Pain Inventory-Short FormPhysical Function Short FormAchilles tendon calcificationHealth-related qualityMajority of patientsCervical spine fusionPresence of enthesopathyAnalgesic medicationRegular chowResidual painAdult patientsDose escalationPhysical functionCardiovascular calcificationTendon calcificationAchilles tendonSpine fusionMurine modelHypophosphatemic ricketsEnzyme replacementPatientsSystematic characterization of enzyme activity on ENPP1 deficiency disease phenotype
Ansh A, Stabach P, Carpenter T, Ferreira C, Braddock D. Systematic characterization of enzyme activity on ENPP1 deficiency disease phenotype. The FASEB Journal 2022, 36 DOI: 10.1096/fasebj.2022.36.s1.r5223.Peer-Reviewed Original ResearchStrategies for Glycoengineering Therapeutic Proteins
Dammen-Brower K, Epler P, Zhu S, Bernstein ZJ, Stabach PR, Braddock DT, Spangler JB, Yarema KJ. Strategies for Glycoengineering Therapeutic Proteins. Frontiers In Chemistry 2022, 10: 863118. PMID: 35494652, PMCID: PMC9043614, DOI: 10.3389/fchem.2022.863118.Peer-Reviewed Original Research
2021
Placenta‐derived interferon‐stimulated gene 20 controls ZIKA virus infection
Ding J, Aldo P, Roberts CM, Stabach P, Liu H, You Y, Qiu X, Jeong J, Maxwell A, Lindenbach B, Braddock D, Liao A, Mor G. Placenta‐derived interferon‐stimulated gene 20 controls ZIKA virus infection. EMBO Reports 2021, 22: e52450. PMID: 34405956, PMCID: PMC8490983, DOI: 10.15252/embr.202152450.Peer-Reviewed Original ResearchConceptsZika virus infectionVirus infectionTrophoblast cellsPotential immune modulatory functionsInterferon-stimulated gene 20Anti-viral treatmentHigh-risk populationImmune modulatory functionsAnti-viral responseZika viral infectionImportance of preventionPregnant womenReplacement therapyViral infectionFetal developmentZika virusViral titersModulatory functionViral replicationInfectionAdverse effectsGene 20PregnancyPlacentaRNA viruses
2020
Musculoskeletal Comorbidities and Quality of Life in ENPP1‐Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models
Ferreira CR, Ansh AJ, Nester C, O'Brien C, Stabach PR, Murtada S, Lester ER, Khursigara G, Molloy L, Carpenter TO, Braddock DT. Musculoskeletal Comorbidities and Quality of Life in ENPP1‐Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models. Journal Of Bone And Mineral Research 2020, 37: 494-504. PMID: 34882836, PMCID: PMC9667476, DOI: 10.1002/jbmr.4487.Peer-Reviewed Original ResearchConceptsENPP1 deficiencyAsj/Musculoskeletal complicationsBrief Pain Inventory-Short FormPhysical Function Short FormFibroblast growth factor 23Achilles tendon calcificationHealth-related qualityMajority of patientsGrowth factor 23Cervical spine fusionPresence of enthesopathyQuality of lifeAnalgesic medicationRegular chowResidual painAdult patientsDose escalationFactor 23Replacement therapyPhysical functionCardiovascular calcificationTendon calcificationAchilles tendonSpine fusionCatalysis‐Independent ENPP1 Protein Signaling Regulates Mammalian Bone Mass
Zimmerman K, Liu X, von Kroge S, Stabach P, Lester ER, Chu EY, Srivastava S, Somerman MJ, Tommasini SM, Busse B, Schinke T, Carpenter TO, Oheim R, Braddock DT. Catalysis‐Independent ENPP1 Protein Signaling Regulates Mammalian Bone Mass. Journal Of Bone And Mineral Research 2020, 37: 1733-1749. PMID: 35773783, PMCID: PMC9709593, DOI: 10.1002/jbmr.4640.Peer-Reviewed Original ResearchConceptsHeterotopic mineralizationBone massFibroblast growth factor 23Growth factor 23Low bone massSoft tissue calcificationEarly-onset osteoporosisFrizzled-related protein 1Soluble Wnt inhibitorsTrabecular bone microarchitectureENPP1 deficiencyΒ-catenin signalingFactor 23Plasma FGF23Vascular calcificationArterial calcificationNuclear β-cateninPlasma PPiBone microarchitectureMurine modelTissue calcificationPlasma PiWnt inhibitorsCalcificationMiceResponse of the ENPP1‐Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice
Ferreira CR, Kavanagh D, Oheim R, Zimmerman K, Stürznickel J, Li X, Stabach P, Rettig RL, Calderone L, MacKichan C, Wang A, Hutchinson HA, Nelson T, Tommasini SM, von Kroge S, Fiedler IA, Lester ER, Moeckel GW, Busse B, Schinke T, Carpenter TO, Levine MA, Horowitz MC, Braddock DT. Response of the ENPP1‐Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. Journal Of Bone And Mineral Research 2020, 36: 942-955. PMID: 33465815, PMCID: PMC8739051, DOI: 10.1002/jbmr.4254.Peer-Reviewed Original ResearchConceptsBone mineral densityLow bone mineral densityTrabecular bone massBone massEarly-onset osteoporosisAsj/Conventional therapyLower trabecular bone massGreater bone fragilityRisk of nephrocalcinosisHigh-phosphate dietLow bone massCortical bone massDevelopment of nephrocalcinosisBone biomechanical propertiesAcademic medical centerPlasma phosphorus concentrationsAutosomal recessive hypophosphatemic ricketsRecessive hypophosphatemic ricketsENPP1 deficiencyRachitic phenotypeMedullary nephrocalcinosisRenal failureNormal chowMineral densityImproving the Pharmacodynamics and In Vivo Activity of ENPP1‐Fc Through Protein and Glycosylation Engineering
Stabach PR, Zimmerman K, Adame A, Kavanagh D, Saeui CT, Agatemor C, Gray S, Cao W, De La Cruz EM, Yarema KJ, Braddock DT. Improving the Pharmacodynamics and In Vivo Activity of ENPP1‐Fc Through Protein and Glycosylation Engineering. Clinical And Translational Science 2020, 14: 362-372. PMID: 33064927, PMCID: PMC7877847, DOI: 10.1111/cts.12887.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArea Under CurveDisease Models, AnimalEnzyme Replacement TherapyGlycosylationHalf-LifeHistocompatibility Antigens Class IHumansMaleMice, TransgenicPhosphoric Diester HydrolasesProtein EngineeringProtein Structure, TertiaryPyrophosphatasesReceptors, FcRecombinant Fusion ProteinsVascular CalcificationConceptsProtein engineeringO-BuN-glycansGlycosylation engineeringCellular recyclingENPP1-deficient miceTerminal sialylationBiomanufacturing platformProtein therapeuticsCalcification disordersSialylationCellsVivo activityFc neonatal receptorTherapeuticsArterial calcificationProteinMurine modelManNAcEnzyme replacementNeonatal receptorEfficacious levelsGeneral strategyThree-prong strategyDrug potencyEnpp1 enzyme replacement restores bone mass in murine model of Enpp1 associated osteoporosis
Braddock D, Kavanagh D, Oheim R, Zimmerman K, Kroge S, Stabach P, Tommasini S, Levine M, Carpenter T, Horowitz M. Enpp1 enzyme replacement restores bone mass in murine model of Enpp1 associated osteoporosis. Bone Reports 2020, 13: 100623. DOI: 10.1016/j.bonr.2020.100623.Peer-Reviewed Original ResearchENPP1 regulates bone mass via an unidentified catalytically independent mechanism
Braddock D, Zimmerman K, Oheim R, Kroge S, Stabach P, Kavanagh D, Tommasini S, Carpenter T. ENPP1 regulates bone mass via an unidentified catalytically independent mechanism. Bone Reports 2020, 13: 100692. DOI: 10.1016/j.bonr.2020.100692.Peer-Reviewed Original ResearchGenetic and pharmacologic modulation of cementogenesis via pyrophosphate regulators
Chu EY, Vo TD, Chavez MB, Nagasaki A, Mertz EL, Nociti FH, Aitken SF, Kavanagh D, Zimmerman K, Li X, Stabach PR, Braddock DT, Millán JL, Foster BL, Somerman MJ. Genetic and pharmacologic modulation of cementogenesis via pyrophosphate regulators. Bone 2020, 136: 115329. PMID: 32224162, PMCID: PMC7482720, DOI: 10.1016/j.bone.2020.115329.Peer-Reviewed Original Research
2019
Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations
Kotwal A, Ferrer A, Kumar R, Singh RJ, Murthy V, Schultz-Rogers L, Zimmermann M, Lanpher B, Zimmerman K, Stabach PR, Klee E, Braddock DT, Wermers RA. Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations. Journal Of Bone And Mineral Research 2019, 35: 662-670. PMID: 31826312, PMCID: PMC7771569, DOI: 10.1002/jbmr.3938.Peer-Reviewed Original ResearchConceptsAutosomal recessive hypophosphatemic rickets type 2Biallelic mutationsMonoallelic mutationsPrimary hyperparathyroidismPathogenic variantsCarotid intima-media thicknessClassic disease manifestationsNormocalcemic primary hyperparathyroidismC-terminal FGF23Intima-media thicknessWhole-exome sequencingClinical findingsArterial calcificationPeriarticular calcificationSpectrum of phenotypesIntact FGF23Disease manifestationsBilateral femursENPP1 variantsBone deformitiesBiochemical manifestationsType 2ENPP1 geneExome sequencingHyperparathyroidismHuman Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency
Oheim R, Zimmerman K, Maulding ND, Stürznickel J, von Kroge S, Kavanagh D, Stabach PR, Kornak U, Tommasini SM, Horowitz MC, Amling M, Thompson D, Schinke T, Busse B, Carpenter TO, Braddock DT. Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency. Journal Of Bone And Mineral Research 2019, 35: 528-539. PMID: 31805212, PMCID: PMC7184798, DOI: 10.1002/jbmr.3911.Peer-Reviewed Original ResearchConceptsAutosomal recessive hypophosphatemic rickets type 2ENPP1 deficiencyEarly-onset osteoporosisGene-dose effectOnset osteoporosisAsj/Bone mineral density scansBone mineralization disturbancesRenal phosphate wastingCortical boneDose effectMild osteomalaciaMineralization disturbancesFGF23 levelsMild elevationPlasma FGF23Arterial calcificationBone massPhosphate wastingSkeletal manifestationsBone fragilityThoracic spineWild-type family membersType 2Adult menProtein Engineering and Glycan Optimization Improves Pharmicokinetics of an Enzyme Biologic 10‐fold
Braddock D, Stabach P, Zimmerman K, Kavanagh D, Sauei C, Yarema K. Protein Engineering and Glycan Optimization Improves Pharmicokinetics of an Enzyme Biologic 10‐fold. The FASEB Journal 2019, 33: 801.1-801.1. DOI: 10.1096/fasebj.2019.33.1_supplement.801.1.Peer-Reviewed Original ResearchFusion proteinProtein engineeringCHO cell linesCellular recyclingBioprocessing methodsRecombinant fusion proteinConsensus sequenceExtracellular domainSialic acidTertiary structureN-acetylmannosamineCHO cellsHuman alphaProteinCell linesFASEB JournalFc domainCell culture mediumCulture mediumGeneralized Arterial CalcificationENPP1
2015
ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy
Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, Covo MS, Tehan M, Yang G, Cheng Z, Bouchard K, Yu ZX, Thorn S, Wang X, Folta-Stogniew EJ, Negrete A, Sinusas AJ, Shiloach J, Zubal G, Madri JA, De La Cruz EM, Braddock DT. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nature Communications 2015, 6: 10006. PMID: 26624227, PMCID: PMC4686714, DOI: 10.1038/ncomms10006.Peer-Reviewed Original ResearchConceptsChronic kidney diseaseVascular calcificationArterial calcificationOrphan diseaseCommon diseaseSequelae of diseaseEctopic vascular calcificationInternal elastic laminaPrevent mortalityRenal failureCardiac failureKidney diseaseSubcutaneous administrationRodent modelsAnimal modelsEctopic calcificationVascular wallLarge arteriesElastic laminaDiseaseCalcificationCalciphylaxisDecreased concentrationSclerosisArtery
2013
Molecular Basis of Purinergic Signal Metabolism by Ectonucleotide Pyrophosphatase/Phosphodiesterases 4 and 1 and Implications in Stroke*♦
Albright RA, Ornstein DL, Cao W, Chang WC, Robert D, Tehan M, Hoyer D, Liu L, Stabach P, Yang G, De La Cruz EM, Braddock DT. Molecular Basis of Purinergic Signal Metabolism by Ectonucleotide Pyrophosphatase/Phosphodiesterases 4 and 1 and Implications in Stroke*♦. Journal Of Biological Chemistry 2013, 289: 3294-3306. PMID: 24338010, PMCID: PMC3916532, DOI: 10.1074/jbc.m113.505867.Peer-Reviewed Original ResearchConceptsExtracellular membrane proteinsMembrane proteinsSubstrate specificityMolecular basisHigh-resolution crystal structuresResolution crystal structureComparative structural analysisATP hydrolysisNPP1Brain vascular endotheliumCorresponding regionTerminal phosphateLow nanomolar concentrationsPurinergic signalsPlatelet aggregationProteinATPEnzymeNanomolar concentrationsVascular endotheliumPhosphodiesterases 4Ap3AMetabolismSurface of chondrocytesTissue mineralization
2011
Cell organization, growth, and neural and cardiac development require αII-spectrin
Stankewich MC, Cianci CD, Stabach PR, Ji L, Nath A, Morrow JS. Cell organization, growth, and neural and cardiac development require αII-spectrin. Journal Of Cell Science 2011, 124: 3956-3966. PMID: 22159418, PMCID: PMC3244980, DOI: 10.1242/jcs.080374.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsAnkyrinsAxonsBody PatterningCarrier ProteinsCell MembraneCell PolarityCell ProliferationCraniofacial AbnormalitiesEmbryo, MammalianEmbryonic DevelopmentFemaleFibroblastsGene DeletionHeart Defects, CongenitalMaleMiceMice, Inbred C57BLMicrofilament ProteinsNeural Tube DefectsNeuroepithelial CellsPhenotypeProtein StabilityPseudopodiaSpectrinConceptsΑII-spectrinSteady-state protein levelsΒIII spectrinEmbryonic day 12.5Tissue patterningRenal epithelial cellsEmbryonic lethalCortical actinOrgan developmentAnkyrin BExon trappingEmbryonic fibroblastsTranscriptional levelΒ-spectrinCardiac developmentCell organizationCell spreadingAxon formationNeural tubeHeterozygous animalsTargeted disruptionApical membraneNeuroepithelial cellsDay 12.5Cell morphology