Katherine P. Ponder, M.D.

Professor
Internal Medicine
Hematology
Biochemistry and Molecular Biophysics

Molecular Genetics and Genomics Program

  • 314-362-5188

  • 314-362-5182

  • 314-362-8813

  • 8125

  • 8818 Clinical Sciences Research Building

  • kponder@wustl.edu

  • http://hematology.im.wustl.edu/people/faculty/Ponder/Ponder_Bio.html

  • blood coagulation, bone and cartilage, cardiovascular physiology, gene therapy, genetics, protease

  • Retroviral vectors for hepatic gene therapy for lysosomal storage diseases and hemophilia

Research Abstract:

Our lab uses hepatic gene therapy to treat recessive genetic deficiencies. We have focused on treating mucopolysaccharidoses, which are lysosomal storage disease due to deficiency of enzymes that degrade glycosaminoglycans (GAGs), which results in multisystemic disease via mechanisms that in general remain unclear. Intravenous injection of a gamma retroviral vector to newborn mice and dogs results in transduction of >2% of hepatocytes, which secrete enzyme with a mannose-6 phosphate tag into blood, which results in high levels of serum activity of a-L-iduronidase (IDUA; deficient in MPS I) or b-glucuronidase (GUSB, deficient in MPS VII). Mannose 6-phosphate-modified enzyme in blood can be taken up by cells throughout the body via the mannose-6 phosphate receptor. This gene therapy approach has reduced many manifestations of disease, although disease in the aorta, heart valves, bone, and cartilage has been difficult to fully correct, which likely relates to their relatively poor blood supply and difficulties with diffusion of the relatively large proteins into the interior. We are currently trying to achieve better delivery to brain using intrathecal injection of AAV vectors. We have also initiated studies to evaluate the pathogenesis of disease in these sites that are difficult to treat. Aortic disease is associated with upregulation of proteins that degrade elastin, which results in elastin fragmentation and aortic dilatation. This is associated with activation of the JAK-STAT pathway, which may be due to activation of toll-like receptors by GAGs. These studies may result in a gene therapy approach for patients with these devastating diseases, or may identify an ancillary treatment for some manifestations such as aortic dilatation.

Selected Publications:

Gurda BL, De Guilhem De Lataillade A, Bell P, Zhu Y, Yu H, Wang P, Bagel J, Vite CH, Sikora T, Hinderer C, Calcedo R, Yox AD, Steet RA, Ruane T, O’Donnell P, Gao G, Wilson JM, Casal M, Ponder KP, Haskins ME. (2015) Evaluation of AAV-mediated gene therapy for central nervous system disease in canine mucopolysaccharidosis VII. Molecular Therapy, in press.

Bradbury AM, Gurda BL, Casal ML, Ponder KP, Vite CH, Haskins ME. A review of gene therapy in canine and feline models of lysosomal storage disorders. Hum Gene Ther Clin Dev. 26:27-37, 2015. PMCID: PMC4516914.

Xing EM, Wu S, Ponder KP. The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice. Molecular Genetics Metabolism 114:209-16, 2015. PMCID: PMC4381425.

Bigg PW, Sleeper MM, O’Donnell PA, Liu Y, Wu S, Casal ML, Haskins ME, Ponder KP. The Effect of Neonatal Gene Therapy with a Gamma Retroviral Vector on Cardiac Valve Disease in Mucopolysaccharidosis VII Dogs after a Decade. Molecular Genetics and Metabolism 110:311-8, 2013. PMCID: PMC3800273.

Bigg PW, Baldo G, Sleeper MM, O’Donnell PA, Bai H, Rokkam VRP, Liu Y, Wu S, Giugliani R, Casal ML, Haskins ME, Ponder KP. Pathogenesis of Mitral Valve Disease in Mucopolysaccharidosis VII Dogs, Molecular Genetics Metabolism, Molecular Genetics and Metabolism 110:319-28, 2013. PMCID: PMC3800211.

Xing EM, Knox VW, O`Donnell PA, Sikura T, Liu Y, Wu S, Casal ML, Haskins ME, Ponder KP. The Effect of Neonatal Gene Therapy on Skeletal Manifestations in Mucopolysaccharidosis VII Dogs after a Decade. Molecular Genetics and Metabolism 109:183-193, 2013. PMCID: PMC3690974.

Metcalf JA, Zhang Y, Hilton MJ, Long F, Ponder KP. Mechanism of Shortened Bones in Mucopolysaccharidosis VII. Molecular Genetics and Metabolism 2009 97: 202-11.

Ponder KP. Immune response hinders therapy for lysosomal storage diseases. Journal Clinical Investigation 2008 118: 2686-2689.

Ma X, Tittiger M, Knutsen RH, Schaller L, Mecham RP, Ponder KP. Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice. Molecular Genetics and Metabolism 2008 94:298-304.

Ponder KP, Haskins ME. Gene therapy for mucopolysaccharidosis. Expert Opinion on Biological Therapy 2007 7: 1333-45.

Last Updated: 9/2/2015 9:37:04 AM

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