Demetrios Braddock, MD, PhD
Associate Professor of Pathology
Research & Publications
Biography
News
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Research Summary
- Vascular Calcification
- Monogenic Enzyme Deficiencies
- Rare Diseases of Childhood
- Biology and Enzymology of Ectonucleotide Pyrophosphatases
- Osteoporosis
- Protein Engineering of Biologic Therapeutics
Specialized Terms; Enzymology; Structural biology; Hematopathology; ENPP1 Deficiency; Murine Models of Rare Diseases
Extensive Research Description
My group is primarily interested in biochemical and structural pathogenesis of blood disorders and protein engineering, and have focused our work on understanding the physiologic role of the ENPP family of enzymes. We recently described two members of the ENPP family in brain vasculature that promote platelet aggregation and calcification. Polymorphisms in one of these enzymes (ENPP1) was recently described to confer stroke protection to pediatric sickle cell patients and a lethal neonatal vascular calcification disorder called 'Generalized Arterial Calcification of Infancy' (GACI). Insights into this pathway allowed us to engineer a curative recombinant biologic which corrects disease sequela in GACI, which are moving into patients in collaboration with a company we founded (Inozyme Pharma). We have also identified a form of early onset osteoporosis associated with ENPP1 deficiency, and are investigating the role of ENPP1 in low bone mass and increased tissue calcification, a medical condition called 'Paradoxical Mineralization' which occurs in the general medical population in conditions such as aging and chronic kidney disease. We have recently expanded our research into enzyme biologics as therapeutics for oncology and autoimmune indications.
Coauthors
Research Interests
Calcification, Physiologic; Osteoarthropathy, Primary Hypertrophic; Pathology; Pseudoxanthoma Elasticum; Sickle Cell Trait; Rare Diseases; Vascular Calcification
Research Image
Molecular Structure, ENPP1 and ENPP4 bound to ATP
Selected Publications
- Response 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, Tommassini SM, von Kroge S, Fiedler IAK, Lester ER, Moeckel GW, Busse B, Schinke T, Carpenter TO, Levine MA, Horwowitz 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 : The Official Journal Of The American Society For Bone And Mineral Research 2021, 36:942-955.
- 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.
- Improving 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 2021, 14:362-372.
- Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization.Maulding ND, Kavanagh D, Zimmerman K, Coppola G, Carpenter TO, Jue NK, Braddock DT. Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. Bone 2021, 142:115656.
- Human 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 : The Official Journal Of The American Society For Bone And Mineral Research 2020, 35:528-539.
- Phylogeny and chemistry of biological mineral transport.Schlesinger PH, Braddock DT, Larrouture QC, Ray EC, Riazanski V, Nelson DJ, Tourkova IL, Blair HC. Phylogeny and chemistry of biological mineral transport. Bone 2020, 141:115621.
- Unraveling the mechanism of recognition of the 3' splice site of the adenovirus major late promoter intron by the alternative splicing factor PUF60.Hsiao HT, Crichlow GV, Murphy JW, Folta-Stogniew EJ, Lolis EJ, Braddock DT. Unraveling the mechanism of recognition of the 3' splice site of the adenovirus major late promoter intron by the alternative splicing factor PUF60. PloS One 2020, 15:e0242725.
- 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 : The Official Journal Of The American Society For Bone And Mineral Research 2020, 35:662-670.
- 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. The Journal Of Biological Chemistry 2014, 289:3294-306.
- NPP4 is a procoagulant enzyme on the surface of vascular endothelium.Albright RA, Chang WC, Robert D, Ornstein DL, Cao W, Liu L, Redick ME, Young JI, De La Cruz EM, Braddock DT. NPP4 is a procoagulant enzyme on the surface of vascular endothelium. Blood 2012, 120:4432-40.
- In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery.Bahal R, Ali McNeer N, Quijano E, Liu Y, Sulkowski P, Turchick A, Lu YC, Bhunia DC, Manna A, Greiner DL, Brehm MA, Cheng CJ, López-Giráldez F, Ricciardi A, Beloor J, Krause DS, Kumar P, Gallagher PG, Braddock DT, Mark Saltzman W, Ly DH, Glazer PM. In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery. Nature Communications 2016, 7:13304.
- MicroRNA silencing for cancer therapy targeted to the tumour microenvironment.Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock DT, Glazer PM, Engelman DM, Saltzman WM, Slack FJ. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 2015, 518:107-10.
- Autotaxin and lipid signaling pathways as anticancer targets.Braddock DT. Autotaxin and lipid signaling pathways as anticancer targets. Current Opinion In Investigational Drugs (London, England : 2000) 2010, 11:629-37.
- Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion.Saunders LP, Ouellette A, Bandle R, Chang WC, Zhou H, Misra RN, De La Cruz EM, Braddock DT. Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion. Molecular Cancer Therapeutics 2008, 7:3352-62.
- Next generation miRNA inhibition using short anti-seed PNAs encapsulated in PLGA nanoparticles.Malik S, Lim J, Slack FJ, Braddock DT, Bahal R. Next generation miRNA inhibition using short anti-seed PNAs encapsulated in PLGA nanoparticles. Journal Of Controlled Release : Official Journal Of The Controlled Release Society 2020, 327:406-419.
- 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.
- Direct targeting of amplified gene loci for proapoptotic anticancer therapy.Kaushik Tiwari M, Colon-Rios DA, Tumu HCR, Liu Y, Quijano E, Krysztofiak A, Chan C, Song E, Braddock DT, Suh HW, Saltzman WM, Rogers FA. Direct targeting of amplified gene loci for proapoptotic anticancer therapy. Nature Biotechnology 2021.