Chester B. Whitley, PhD, MD Delivered Keynote Address on Wednesday, February 12, 2019

WORLDSymposium was pleased to announce Chester (Chet) B. Whitley, Ph.D., M.D., as the Keynote Speaker for Thursday, February 7, 2019. Dr. Whitley is a tenured Professor in the Department of Pediatrics, the Department of Experimental and Clinical Pharmacology, and Director of the Advanced Therapies Program at the University of Minnesota.

In 1983, Dr. Whitley conducted the first U.S. trials of bone marrow transplantation for Hurler syndrome, other mucopolysaccharidoses, and selected lysosomal diseases including Krabbe disease, Tay-Sachs disease. With the first transplant for Hurler syndrome in the U.S.A. (September 13, 1983, University of Minnesota)1 and the continuing clinical trials during the next decade,2 he characterized the level of response and clinical outcomes. In the case of Hurler syndrome, cognitive testing and imaging showed protection of the brain despite the seemingly impenetrable blood-brain barrier. Being the very first efficacious treatment for a lysosomal disease, this procedure of hematopoietic stem transplant provided the proof-of-principle for development of future enzyme replacement therapies, gene therapy, and other systemic treatments. During these early transplant studies, Dr. Whitley expanded upon the 1960’s “cross-correction” observations at NIH in cultured fibroblasts, and coined the term “metabolic cross-correction”1 and characterized multiple different mechanisms accounting for the clinical responses in patients. In conversation with the U.S.F.D.A. in the early 1990’s, he coined the term “ultra-orphan disease” to differentiate those conditions that are orders of magnitude more rare than the legislated definition of “orphan disease” with prevalence of <200,000.

Dr. Whitley directs the CLIA-certified Gene Therapy and Diagnostics Lab, the first laboratory in North America to offer complete sequencing of a gene to be offered as a ‘clinical diagnostic’ (non-research) test.

In the late 1990s, Dr. Whitley conducted the first clinical trial of gene therapy for a mucopolysaccharidosis condition, Hunter syndrome.3 At that time, he invented4 the DMB dye-binding test for measuring urine glycosaminoglycans (GAG), the most common method for quantifying GAG in diagnostic laboratories globally.

He is also responsible for a number of other ‘firsts’: (a) discovering a ‘pseudo-deficiency’ allele for MPS5,6; (b) finding that combining therapies, e.g., enzyme replacement therapy (ERT) after bone marrow transplantation7 may enhance metabolic correction; (c) demonstrating that small amounts of intravenous laronidase enzyme cross the blood-brain barrier and reduces the pathology in the brain, and improves the learning of mice with Hurler syndrome8; and, recently, that (d) intravenous zinc-finger nuclease gene-editing prevents brain disease in mice with Hurler syndrome9 and Hunter syndrome10.

Dr. Whitley conceived and organized the 1st International Symposium on Mucopolysaccharidosis and Related Diseases (May 20-23, 1988, Minneapolis, Minnesota).11 He is also Director of the Gene Therapy Center at the University of Minnesota supported by an NIH program project grant Gene Therapy for Metabolic Disease for two decades (5P01HD032652).

He is the founding Principal Investigator of the NIH-funded Lysosomal Disease Network currently coordinating 21 clinical studies at 18 institutions. Dr. Whitley is the founding organizer (May 12-15, 2004, Minneapolis, MN USA) and current Course Director of the annual We’re Organizing Research on Lysosomal Diseases scientific meeting ‘WORLDSymposia’ an international forum that fuses basic, translational and clinical research on lysosomal diseases.

On Thursday, February 7, 2019, at 7:30 AM, Dr. Whitley’s Keynote Address The ‘New’ Lysosomal Disease Network, described how the intersection of past lysosomal disease research and current, ongoing, unmet need, has created both the springboard for the next generations of therapies, and provided the overarching vision for researchers and clinicians in the LDN going forward.

  1. Whitley CB, Ramsay NKC, Kersey JH, Krivit W: Bone marrow transplantation for Hurler syndrome. Assessment of metabolic correction. Birth Defects 22:7-24, 1986.
  2. Whitley CB, Belani K, Chang PN, Summers CG, Blazar BR, Tsai MY, Latchaw RE, Ramsay NKC, Kersey JH: Long-term outcome of Hurler syndrome following bone marrow transplantation, Am J Med Genet 46:209-218, 1993.
  3. U.S. Food and Drug Administration BB-IND: #5370; Autologous Peripheral Blood Stem Cells Cultured Ex-Vivo with Anti-CD3 (OKT3, Ortho) and Interleukin-2 (Chiron); Transduced (L2SN, University of Minnesota) Expressing IDS Gene; approved to initiate clinical trial (June, 1995). Active clinical trial period: – January 10, 1998.
  4. NIH Recombinant DNA Advisory Committee application; Retroviral-Mediated Transfer of the Iduronate-2-Sulfatase Gene Into Lymphocytes for Treatment of Mild Hunter Syndrome (Mucopolysaccharidosis Type II), Human Gene Therapy Protocol, University of Minnesota Medical School, Minneapolis, MN, Chester B. Whitley, Ph.D., M.D., R. Scott McIvor, Ph.D., Susan A. Berry, M.D., Bruce R. Blazar, M.D., John H. Kersey, M.D., Richard A. King, M.D., Ph.D., Anthony J. Faras, Ph.D., Richard E. Latchaw, M.D., Jeffrey J. McCullough, M.D.,
    Norma K.C. Ramsay, M.D.
  5. Method for the Detection of Mucopolysaccharide Disease (Serial No. 194,553) submitted May 13, 1988; continuation-in-part (Serial No. 07/297,051) submitted January 16, 1989; amendment, Method for the detection of mucopolysaccharide storage disease, continuation-in-part (Serial No. 07/297,051) submitted May 29, 1991; patent allowed, November, 1993; patent application (Serial No. 07/806,833) Method for the Detection of Mucopolysaccharide Storage Diseases issued on May 10, 1994 as U.S. Patent No. 5,310,646.
  6. Whitley CB, Gorlin RJ, Krivit W. A nonpathologic allele (IW) for low alpha-L-iduronidase enzyme activity vis-a-vis prenatal diagnosis of Hurler syndrome. Am J Med Genet 28(1). 1987. 233-243. PMID: 3118714.
  7. Aronovich EL, Pan D, Whitley CB, Molecular genetic defect underlying alpha-L-iduronidase pseud
    odeficiency. Am J Hum Genet. 1996 Jan;58(1):75-85. PMCID: PMC1914939.
  8. Whitley CB, Utz JR. Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI): a single dose of galsulfase further reduces urine glycosaminoglycans after hematopoietic stem cell transplantation. Mol Genet Metab 101(4). 2010. 346-348. PMID: 20800524.
  9. Ou, L., DeKelver R.C., Rohde M., Tom S., Radeke R., St. Martin S., Santiago,Y, Sproul S., Przybilla M.J., Koniar B.L., Podetz-Pedersen K.M., Laoharawee K., Cooksley R.D., Meyer K.E., Holmes M.C., McIvor R.S., Wechsler T., Whitley C.B. ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome, Molecular Therapy (2018), doi: https://doi.org/10.1016/j.ymthe.2018.10.018.
  10. Ou, L., DeKelver R.C., Rohde M., Tom S., Radeke R., St. Martin S., Santiago,Y, Sproul S., Przybilla M.J., Koniar B.L., Podetz-Pedersen K.M., Laoharawee K., Cooksley R.D., Meyer K.E., Holmes M.C., McIvor R.S., Wechsler T., Whitley C.B. ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome, Molecular Therapy (2018), doi: https://doi.org/10.1016/j.ymthe.2018.10.018.
  11. K. Laoharawee, R. DeKelver, K. Podetz-Pedersen, M. Rohde, S. Sproul, H. Nguyen, T. Nguyen, S.S. Martin, L. Ou, S. Tom, C.B. Whitley, R.S. McIvor. Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-mediated In Vivo Genome Editing. Molecular Therapy 26(4):1127-1136, April 2018. doi.org/10.1016/j.ymthe.2018.03.002
  12. Whitley, CB, J.M. Opitz, J.F. Reynolds. First International Congress on Mucopolysaccharidosis and Related Diseases ‐ 70 Years of Research, University of Minnesota, Minneapolis, May 20–23, 1988. Am J Med Genet 32(2) 1989. doi.org/10.1002/ajmg.1320320233