Glenn Niemeyer
Research Interests Dr. Niemeyer’s research has two major areas of emphasis: gene therapy of blood diseases and studies examining the molecular events associated with hematopoietic stem cell biology. Gene Therapy Hemophilia.Hemophilia is an ideal target disease for gene therapy because factor VIII or IX concentrations as low as two to five percent of normal will be sufficient to correct the severe hemophilia phenotype. One of the greatest concerns for gene replacement therapies is that the expressed therapeutic protein may be immunogenic. In many regards, the immunological hurdle to gene therapy has much in common to immunological issues associated with cellular and solid organ transplantation. Therefore, we have applied methodologies we have developed for tolerance induction in other models to the dog hemophilia model. The goal of this current research is to determine if nonmyeloablative conditioning and transient immunosuppression, which apparently induces tolerance to renal allografts and bone marrow, will also result in tolerance to unique protein antigens such as factor IX. This area of research is a natural extension of the exciting recent progress made in two distinct fields: nonmyeloablative conditioning for mixed chimerism and transplantation tolerance induction and gene therapy as a treatment for hemophilia. Canine Cyclic Hematopoiesis.Cyclic hematopoiesis (CH) is an unusual disorder of the hematopoietic stem cell that causes regular oscillations in the number of circulating blood cells. The hallmark of CH is the cyclic neutropenia that occur at 14 and 21 day intervals in dogs and humans, respectively. Recently, in collaboration with the Horowitz laboratory (University of Washington School of Medicine, Seattle, Washington) we have shown that canine CH is caused by a mutation in the AP3b1gene which encodes the b3a subunit of the adaptor complex-3 (AP3). AP3 specifically shuttles transmembrane “cargo” proteins from the trans-Golgi to lysosomes. Mutations in AP3b1 and neutrophil elastase (ELA2) cause similar illnesses in humans. Additional studies showed that AP3 recognizes neutrophil elastase as a cargo protein and normally traffics it to granules. Current studies are in progress to address our hypothesize that abnormal elastase localization at the plasma membrane (rather than granules) causes increased proteolytic degradation of membrane receptors and a dampened proliferative response in myeloid progenitor cells which unmasks the inherent cyclic nature of hematopoiesis Publications Niemeyer GP, Hudson J, Dufresne MM, Bridgeman R, Nash R, and Lothrop CD Jr.: Isolation and characterization of canine hematopoietic progenitor cells. Exp. Hematol  29(6):686-93, 2001 Zaucha JA, Yu C, Lothrop CD, Nash RA, Sale G, Georges G, Kiem HP, Niemeyer GP, Dufresne M, Cao Q, Storb R.  Severe canine hereditary hemolytic anemia treated by nonmyeloablative marrow transplantation.  Biol Blood Marrow Transplant, 7:14-24, 2001. Bensen KF, Li FQ, Albani PD, Duan AZ, Wechsler J, Meade-White K, Williams K, Acland GM, Niemeyer GP, Lothrop CD, Jr., and Horwitz M: Canine Cyclic Hematopoiesis: Dog and Human Neutropenia Mutations Disrupt Intracellular Transport of Neutrophil Elastase. Nature Genetics, 35:90-96, 2003 Niemeyer GP, Boudreaux MK, Goodman-Martin SA, Monroe CM, Wilcox DA, and Lothrop CD , Jr.: Correction of a Large Animal Model of Type I Glanzmann’s Thrombasthenia by Nonmyeloablative Bone Marrow Transplantation. Exp Hematol, 31:1357-1362, 2003 Niemeyer GP, Welch JA, Tillson DM, Holland M, Brawner WR, Rynders P, Goodman-Martin SA, Dufresne M, Dennis J, and Lothrop CD, Jr.: Renal Allograft Tolerance in DLA-Identical and Haploidentical Dogs after Nonmyeloablative Conditioning and Transient Immunosuppression with Cyclosporin and Mycophenolate Mofetil.  Transplantation Proceedings, 37(10):4579-86, 2005 Niemeyer GP, Herzog R, Mount J, Arruda V, Tillson M, Hathcock J, van Ginkel F, High K, Lothrop CD, Jr.  Long Term Correction of Inhibitor Prone Hemophilia B Dogs Treated with Liver-Directed AAV2 Mediated Factor IX Gene Therapy.  (Submitted: Blood, 2008)