Dr. Christian Fernandez is an Assistant Professor at Department of Pharmaceutical Sciences and a member of the Center for Pharmacogenetics at the University of Pittsburgh School of Pharmacy. He received his Ph.D. from the University of Iowa College of Pharmacy, and he completed his postdoctoral fellowship with Dr. Mary Relling at St. Jude Children's Research Hospital.
The research in the laboratory of Dr. Fernandez focuses on the pharmacogenomics of adverse drug reactions. The immunogenicity of protein-based therapeutics is a major problem that can lead to life-threatening complications and reduce or eliminate the therapeutic effects of biologics. The objectives of Dr. Fernandez’s research are to elucidate the mechanism of adverse drug reaction by identifying polymorphisms (variations) in genes that can explain why certain patients are predisposed to developing immune responses to biologics, to identify therapeutic strategies that can block and maintain therapeutic drug concentrations, and to develop clinical laboratory tests that can monitor drug bioavailability and immunogenicity to indicate when a drug substitution is appropriate.
Dr. Fernandez has extensively studied the immune response to the chemotherapeutic agent, asparaginase, which is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. Up to 70% of children have been reported to develop anti-asparaginase antibodies during treatment, and the immune response to asparaginase has been linked to a higher risk of relapse. The research in the Fernandez lab aims to identify therapeutic strategies to mitigate the response and extend asparaginase exposure after a reaction in order to improve the risk of relapse among these patients.
His research has led to the development of a high throughput assay for the therapeutic drug monitoring of asparaginase serum concentrations, the development of a murine model of asparaginase hypersensitivity for identifying strategies to restore asparaginase drug exposure after an immune response, and his pharmacogenomics studies have linked the NFAT pathway with the risk of developing asparaginase-induced hypersensitivity, which he is currently investigating as a possible drug target to attenuate the immune response to protein-based therapeutics.
Along with other collaborators at the University of Pittsburgh he is currently developing a novel method for monitoring the immunogenicity of biologics used in the treatment of rheumatoid arthritis, such as adalimumab, etanercept, and infliximab. The aims of this research are to determine whether anti-TNFi biologic antibody levels correlate with plasma drug concentrations and efficacy, to identify genetic variants that may predispose patients to the development of anti-TNFi biologic antibodies, and to elucidate how various TNFi biologics should be used in the clinic after the development of anti-drug antibodies to improve efficacy and avoid the use of TNFi biologics with no therapeutic benefit.
Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, Basford M, Bastarache L, Roden DM, Denny JC, Larsen E, Winick N, Carroll WL, Cheng C, Pei D, Fernandez CA, Liu C, Smith C, Loh ML, Raetz EA, Hunger SP, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Mattano LA Jr, Relling MV. Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2015 Oct 8;126(15):1770-6. doi: 10.1182/blood-2015-05-643601. Epub 2015 Aug 11. PubMed PMID: 26265699.
Fernandez CA, Smith C, Yang W, Mullighan CG, Qu C, Larsen E, Bowman WP, Liu C, Ramsey LB, Chang T, Karol SE, Loh ML, Raetz EA, Winick NJ, Hunger SP, Carroll WL, Jeha S, Pui CH, Evans WE, Devidas M, Relling MV. Genome-wide analysis links NFATC2 with asparaginase hypersensitivity. Blood. 2015 Jul 2;126(1):69-75. doi: 10.1182/blood-2015-02-628800. Epub 2015 May 18. PubMed PMID: 25987655; PubMed Central PMCID: PMC4492197.
Paugh SW, Bonten EJ, Savic D, Ramsey LB, Thierfelder WE, Gurung P, Malireddi RK, Actis M, Mayasundari A, Min J, Coss DR, Laudermilk LT, Panetta JC, McCorkle JR, Fan Y, Crews KR, Stocco G, Wilkinson MR, Ferreira AM, Cheng C, Yang W, Karol SE, Fernandez CA, Diouf B, Smith C, Hicks JK, Zanut A, Giordanengo A, Crona D, Bianchi JJ, Holmfeldt L, Mullighan CG, den Boer ML, Pieters R, Jeha S, Dunwell TL, Latif F, Bhojwani D, Carroll WL, Pui CH, Myers RM, Guy RK, Kanneganti TD, Relling MV, Evans WE. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet. 2015 Jun;47(6):607-14. doi: 10.1038/ng.3283. Epub 2015 May 4. PubMed PMID: 25938942; PubMed Central PMCID: PMC4449308.
Fernandez CA, Smith C, Karol SE, Ramsey LB, Liu C, Pui CH, Jeha S, Evans WE, Finkelman FD, Relling MV. Effect of premedications in a murine model of asparaginase hypersensitivity. J Pharmacol Exp Ther. 2015 Mar;352(3):541-51. doi: 10.1124/jpet.114.220780. Epub 2015 Jan 8. PubMed PMID: 25573198; PubMed Central PMCID: PMC4352598.
Fernandez CA, Smith C, Yang W, Daté M, Bashford D, Larsen E, Bowman WP, Liu C, Ramsey LB, Chang T, Turner V, Loh ML, Raetz EA, Winick NJ, Hunger SP, Carroll WL, Onengut-Gumuscu S, Chen WM, Concannon P, Rich SS, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Relling MV. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014 Aug 21;124(8):1266-76. doi: 10.1182/blood-2014-03-563742. Epub 2014 Jun 26. PubMed PMID: 24970932; PubMed Central PMCID: PMC4141516.
Fernandez CA, Stewart E, Panetta JC, Wilkinson MR, Morrison AR, Finkelman FD, Sandlund JT, Pui CH, Jeha S, Relling MV, Campbell PK. Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase. Cancer Chemother Pharmacol. 2014 Jun;73(6):1307-13. doi: 10.1007/s00280-014-2464-2. Epub 2014 Apr 27. PubMed PMID: 24771103; PubMed Central PMCID: PMC4137479.
Fernandez CA, Cai X, Elozory A, Liu C, Panetta JC, Jeha S, Molinelli AR, Relling MV. High-throughput asparaginase activity assay in serum of children with leukemia. Int J Clin Exp Med. 2013 Aug 1;6(7):478-87. Print 2013. PubMed PMID: 23936585; PubMed Central PMCID: PMC3731178.
Liu C, Kawedia JD, Cheng C, Pei D, Fernandez CA, Cai X, Crews KR, Kaste SC, Panetta JC, Bowman WP, Jeha S, Sandlund JT, Evans WE, Pui CH, Relling MV. Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia. 2012 Nov;26(11):2303-9. doi: 10.1038/leu.2012.102. Epub 2012 Apr 9. PubMed PMID: 22484422; PubMed Central PMCID: PMC3516853.
Hicks JK, Crews KR, Hoffman JM, Kornegay NM, Wilkinson MR, Lorier R, Stoddard A, Yang W, Smith C, Fernandez CA, Cross SJ, Haidar C, Baker DK, Howard SC, Evans WE, Broeckel U, Relling MV. A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record. Clin Pharmacol Ther. 2012 Nov;92(5):563-6. doi: 10.1038/clpt.2012.140. Epub 2012 Sep 19. PubMed PMID: 22990750; PubMed Central PMCID: PMC3589522.
Fernandez CA, Smith C, Yang W, Lorier R, Crews KR, Kornegay N, Hicks JK, Stewart CF, Kawedia JD, Ramsey LB, Liu C, Evans WE, Relling MV, Broeckel U. Concordance of DMET plus genotyping results with those of orthogonal genotyping methods. Clin Pharmacol Ther. 2012 Sep;92(3):360-5. doi: 10.1038/clpt.2012.95. Epub 2012 Aug 8. PubMed PMID: 22871999; PubMed Central PMCID: PMC3516299.
Kawedia JD, Liu C, Pei D, Cheng C, Fernandez CA, Howard SC, Campana D, Panetta JC, Bowman WP, Evans WE, Pui CH, Relling MV. Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood. 2012 Feb 16;119(7):1658-64. doi: 10.1182/blood-2011-09-381731. Epub 2011 Nov 23. PubMed PMID: 22117041; PubMed Central PMCID: PMC3286344.
Fernandez CA, Baumhover NJ, Duskey JT, Khargharia S, Kizzire K, Ericson MD, Rice KG. Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver. Gene Ther. 2011 Jan;18(1):23-37. doi: 10.1038/gt.2010.117. Epub 2010 Aug 19. PubMed PMID: 20720577; PubMed Central PMCID: PMC2990782.
Anderson K, Fernandez C, Rice KG. N-glycan targeted gene delivery to the dendritic cell SIGN receptor. Bioconjug Chem. 2010 Aug 18;21(8):1479-85. doi: 10.1021/bc1000824. PubMed PMID: 20715853.
Fernandez CA, Baumhover NJ, Anderson K, Rice KG. Discovery of metabolically stabilized electronegative polyacridine-PEG peptide DNA open polyplexes. Bioconjug Chem. 2010 Apr 21;21(4):723-30. doi: 10.1021/bc900514s. PubMed PMID: 20218669; PubMed Central PMCID: PMC2860281.
Baumhover NJ, Anderson K, Fernandez CA, Rice KG. Synthesis and in vitro testing of new potent polyacridine-melittin gene delivery peptides. Bioconjug Chem. 2010 Jan;21(1):74-83. doi: 10.1021/bc9003124. PubMed PMID: 19968269; PubMed Central PMCID: PMC2813064.
Fernandez CA, Rice KG. Engineered nanoscaled polyplex gene delivery systems. Mol Pharm. 2009 Sep-Oct;6(5):1277-89. doi: 10.1021/mp900033j. Review. PubMed PMID: 19385668.