We propose to continue and expand the clinical research and training programs of the Porphyrias Consortium (PC), a currently funded Consortium of the Rare Disease Clinical Research Network (RDCRN) that focuses on the inborn errors of heme biosynthesis, the porphyrias. The PC has brought together the complementary strengths of the senior porphyria experts at six regional centers;the American Porphyria Foundation (APF), the only US porphyria patient advocacy and support group;and biopharmaceutical companies interested in improving diagnosis and/or developing novel therapies for these diverse diseases. The Principal Investigator and Administrative Director will be Robert J. Desnick, PhD, MD, Icahn School of Medicine at Mount Sinai (MSSM) and Karl E. Anderson, MD, University of Texas Medical Branch, Galveston, respectively. The other four Consortium Directors are D. Montgomery Bissell, MD, University of California at San Francisco (UCSF);Joseph R. Bloomer, MD, University of Alabama at Birmingham (UAB);Herbert L. Bonkovsky, MD, Carolinas HealthCare System (CHS);and John Phillips, PhD, University of Utah (UoU). These porphyria experts form an interactive and interdisciplinary team of translational and clinical investigators who have active basic and clinical porphyria research programs, strong track records for training young investigators, and internationally recognized clinical expertise. For the past four years, they have worked as an effective team to accomplish the original objectives of the PC as documented in the progress reports for each project. The PC recruited over 450 patients in less than three years to the Longitudinal Study (LS) to document the natural history of each porphyria, and initiated six other clinical studies or trials, and a pilot/demonstration project. We will continue to enroll patients into the LS and other studies through the Contact Registry, APF and physician referrals, and the establishment of Outreach Clinics. In addition, we will continue training the next generation of porphyria experts, supported by $1.5 million in matching grants donated by patients and industry. New studies will focus on the acute hepatic porphyrias, including a project to identify safe new drugs and an in-depth observational study prior to clinical trials of Panhematin(r) and a novel RNA interference therapy. The pilot/demonstration program will include investigation of porphyria candidate modifier genes, Skype-based focus groups, and an exosome assay for hepatic ALAS1. These studies should lead to more effective management and treatment of these diseases.
The hepatic and erythropoietic porphyrias are rare inborn errors of heme biosynthesis that are or unrecognized or misdiagnosed, and in need of improved and specific therapies. Their rarity has limited characterization of their clinical manifestations, natural histories and genotype/phenotype correlations. This Consortium brings together senior porphyria experts at six academic institutions, the APF, and industry to address these limitations by enrolling biochemically- and mutation-confirmed porphyria patients in the current and proposed clinical studies and trials. We also will continue to train porphyria clinicians and researchers.
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|Singal, Ashwani K; Parker, Charles; Bowden, Christine et al. (2014) Liver transplantation in the management of porphyria. Hepatology 60:1082-9|
|Yasuda, Makiko; Gan, Lin; Chen, Brenden et al. (2014) RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci U S A 111:7777-82|
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|Wang, Lejin; Wang, Lejing; He, Fei et al. (2012) ABCB6 mutations cause ocular coloboma. Am J Hum Genet 90:40-8|
|Phillips, John D; Kushner, James P; Bergonia, Hector A et al. (2011) Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol Dis 47:249-54|
|Hasanoglu, Alev; Balwani, Manisha; Kasapkara, Cigdem S et al. (2011) Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. J Inherit Metab Dis 34:225-31|
|Machaczka, Maciej; Klimkowska, Monika; Regenthal, Sofie et al. (2011) Gaucher disease with foamy transformed macrophages and erythrophagocytic activity. J Inherit Metab Dis 34:233-5|
|Balwani, Manisha; Grace, Marie E; Desnick, Robert J (2011) Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)--RecNcil allele. J Inherit Metab Dis 34:789-93|
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