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Molecular Medicine Program
Director: Tracey A. Rouault, MD
The Molecular Medicine Program (MMP) strives to identify causes and pathophysiology of rare human diseases and evaluate novel treatment approaches though preclinical testing of new molecular entities and by performing clinical trials. Metabolic disorders that affect hematopoiesis and cause neurodegeneration are common themes. The MMP seeks to apply cutting-edge basic science methods to understand normal and abnormal metabolism, and improve health by identifying promising potential solutions, including gene therapy, which can be developed and tested in humans.
Stephen Kaler's Section on Translational Neuroscience investigates the genetic causes of inherited copper transport diseases and how the responsible genes participate in neurologic processes. The laboratory seeks to dissect and understand disease mechanisms and to use knowledge gained to improve health through rational treatments, including gene therapy. Kaler identified the molecular basis for occipital horn syndrome and, with international collaborators, delineated the causes of several other conditions affecting copper homeostasis, including ATP7A-related isolated distal motor neuron degeneration, and unique syndromes due to mutations in SLC33A1 (an acetylCoA transporter), CCS (a copper chaperone), and AP1S1 (adapter protein complex 1 sigma subunit). The Unit pioneered early identification of infants at-risk for Menkes disease, using plasma neurochemical measurements, and developed a predictive test for responsiveness to copper treatment of this illness based on residual copper transport activity by certain mutant ATP7A alleles in a yeast complementation assay. The Unit recently rescued a lethal mouse model of Menkes disease by brain-directed adeno-associated virus (AAV)–mediated gene addition. Extension of these latter proof-of-concept investigations, in tandem with preclinical toxicology studies, will pave the way for a first-in-human gene therapy trial for Menkes disease patients with complete loss-of-function ATP7A gene defects. The Unit is also working to distinguish the mechanisms responsible for normal copper transport activity from those of intracellular trafficking of ATP7A and of ATP7B, a closely related copper-transporting ATPase.
Using mouse models and tissue culture, Tracey Rouault's Section on Human Iron Metabolism studies mammalian iron metabolism. Rouault previously identified and characterized two major cytosolic iron-regulatory proteins (IRP). Targeted deletion of each IRP in mice revealed that misregulation of iron metabolism resulting from loss of IRP2 causes functional iron deficiency, erythropoietic protoporphyria, anemia, and neurodegeneration, which adversely affects motor neurons in particular. The Section also focuses on mammalian iron sulfur cluster assembly because of its relevance to IRP1 regulation. IRP1–deficient mice develop polycythemia and pulmonary hypertension because of translational derepression of HIF2 alpha. Researchers in the Section characterized numerous mammalian genes involved in iron-sulfur cluster synthesis and developed in vitro and in vivo methods to assess iron sulfur cluster biogenesis. The Section's discoveries may promote understanding and treatment of neurodegenerative diseases, especially Parkinson's disease and Friedreich's ataxia, and hematologic disorders such as refractory anemias and erythropoietic protoporphyria. The Section discovered that the use of Tempol, a stable nitroxide, prevents neurodegeneration in a mouse deficient in IRP2. Using newly developed antisense technology and genetic engineering of stem cells derived from patients with genetic diseases, the Section is pursuing studies to elucidate the pathophysiology and develop treatments for three diseases caused by defects in iron sulfur cluster biogenesis, including Friedreich's ataxia, ICSU (iron-sulfur cluster assembly enzyme) deficiency myopathy, and GLRX5 sideroblastic anemia, as well as mutations in the NFU gene. The Section is also studying cancers caused by mutations in succinate dehydrogenase subunit B and fumarate hydratase, with emphasis on understanding metabolic remodeling, including changes in iron metabolism that accompany the switch to aerobic glycolysis in cancer.