How genetic and genomic analysis are leading to new therapies in Kawasaki disease

Date: 

Fri Feb 21, 2014

Host: 

Jane Burns
UCSD School of Medicine, Dept. of Pediatrics

Category: 

Kawasaki Disease (DBP 4)

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ABSTRACT

Our first genetic studies of Kawasaki disease (KD) began in 1998 when we found a skewed distribution of two single nucleotide polymorphisms (SNPs) in the promoter region of TNFα that were potentially implicated in increased gene expression. These early observations inspired a small clinical trial of pentoxifylline, a modulator of TNFα mRNA synthesis, and the first KD patient was treated at UCSD in 1998. Since those early days, the recognition of the amazing complexity of the factors regulating gene expression makes these early studies seem very naïve. However, subsequent genomic studies continued to support the concept that the TNFα signaling pathway was a key driver of inflammation in KD, and in 2002, the first KD patient was treated at UCSD with infliximab, a monoclonal antibody against TNFα. Next month, the results of our Phase III clinical trial of infliximab in KD patients will be published, which demonstrate that infliximab plus intravenous immunoglobulin (IVIG) treatment results in more rapid reduction of fever and inflammatory markers and more rapid resolution of coronary artery dilation compared to IVIG alone. Development of stream-lined genotyping techniques, the advent of microarray profiling of gene expression, and the formation of an international collaboration to pool DNA samples from KD patients and their biologic parents accelerated the pace of discovery and lead to studies showing the central role of the TGFβ signaling pathway and its link to myofibroblast transformation and recruitment of inflammatory cells into the vessel wall. This in turn led to the current clinical trial of atorvastatin as an inhibitor of endothelial/epithelial to mesenchymal transformation. Results from a genome-wide linkage study in Japanese siblings concordant for KD led to the discovery of a functional SNP in a NFAT/calcineurin calcium signaling pathway that led us to try cyclosporine, a specific inhibitor of calcineurin, as a treatment for highly resistant KD patients. The success of this alternative therapy for refractory KD patients was published by our group in 2012. Association studies, GWAS, and targeted sequencing (funded by iDASH through DBP1) further implicated the TGFβ and calcineurin/NFAT signaling pathways in disease pathogenesis. The newest clinical trial is based on microarray experiments that consistently pointed to the IL-1β signaling pathway as a major pro-inflammatory motif in acute KD patients. We are in the process of applying for an IND from the FDA for a trial of anakinra, a recombinant IL-1 receptor antagonist that competitively binds IL-1β, thus reducing IL-1β signaling. Thus, our genetic/genomic studies have led us to try five new therapies for KD, which we hope will usher in a better future for our patients.

 

SPEAKER BIOGRAPHY

Dr. Jane C. Burns is a native of San Francisco, California. She received her M.D. degree at the University of North Carolina in Chapel Hill in 1978 and completed her pediatric residency and Chief Residency at the University of Colorado School of Medicine in Denver, Colorado. In 1983, Dr. Burns moved to Harvard Medical School and the Boston Children’s Hospital for additional training in pediatric infectious diseases and molecular virology. She joined the faculty at Harvard in 1986 and in 1990 moved to San Diego, California, where she joined the faculty at the University of California as an Assistant Professor. Dr. Burns moved up through the ranks and was appointed Professor of Pediatrics in 1999. She was appointed Chief of the Division of Allergy, Immunology, and Rheumatology in 2000. Currently, Dr. Burns is Director of the Kawasaki Disease Research Center at UCSD/Rady Children’s Hospital where she leads a multidisciplinary team that cares for 80-90 new Kawasaki disease patients each year and follows over 1,200 families in the KD Clinic. Her passion for studies of Kawasaki disease has spanned almost three decades with her first publication on KD in 1982. In addition to her academic pursuits, Dr. Burns is the mother of two daughters. Her husband, John B. Gordon M.D., is an interventional cardiologist who cares for adults with long-term sequelae of KD. Together, Burns and Gordon with a team from UCSD have launched The Adult KD Collaborative, a long-range epidemiologic and clinical study of cardiovascular biomarkers and functional studies in adults who suffered from KD in childhood.

 

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