Disease Programs

Hematopoietic Stem Cells And Immunology

Janis Abkowitz (Hematology, Medicine)

Dr. Abkowitz studies the in vivo behavior of hematopoietic stem cells (HSC) in transplantation models and in parabiotic mice. She has shown that the divergent patterns of clonal contribution in individual animals following limiting dilution transplantation can be explained by the stochastic differentiation of HSC and has investigated the mechanism by which neoplastic HSC dominate in the myeloproliferative disorders. She also studies the pathogenesis and therapy of erythroid marrow failure and the role of heme export in this process.

Pamela S Becker (Hematology, Medicine)

Hematopoietic stem cell transplant

Anthony Blau (Co-director, ISCRM; Hematology, Medicine)

This lab works on developing small molecule control mechanisms to regulate the number of cells in a patient after transplant, thereby increasing or decreasing cell number based on clinical end points.

David Emery (Hematology, Medicine)

Research in the Emery laboratory is focused on basic and translational research in the field of hematopoietic stem cell gene therapy. One major area of interest involves the development of recombinant virus vectors for therapeutic globin genes and the testing of these vectors in mouse and non-human primate models. This includes in part the use of transgenic mouse models of beta-thalassemia intermedia and beta-thalassemia major to study the transfer, expression, and biological function of candidate vectors. Another major area of interest includes the identification, characterization, and application of chromatin insulators in order to improve the efficacy and safety of recombinant virus vectors. This includes in part the use of genetic screens and informatics to identify potential insulators, the study of insulator activity on chromatin structure, and the development of novel tumor formation assays to study vector-related genotoxicity.

Andrew G. Farr (Biological Structure & Immunology)

Thymic epithelial differentiation. The focus of this laboratory is to understand the developmental program of thymic epithelial cells. This knowledge is critical for developing strategies to enhance the recovery of thymic epithelium from the conditioning strategies employed in bone marrow transplantation, for the reversal of age-related senescence of thymic function, and to understand how the thymus contributes to the establishment and maintenance of self-tolerance. Approaches include the identification of thymic epithelial populations with regenerative capacity in vitro or in vivo and the use of modified embryonic stem cells as candidate thymic epithelial progenitor cells. Information gained from murine studies will be translated to the human.

 

Hans-Peter Kiem (FHCRC)

The main focus of our lab is to study stem cell biology and stem cell gene transfer with the goal of developing novel stem cell based treatment strategies for patients with genetic, infectious and malignant diseases. Most of our work has been with hematopoietic stem cells (HSCs) although more recently we have also initiated studies using embryonic stem (ES) cells. Our lab has focused on studying HSC biology and gene transfer in large animal models.

The following are some of the projects in the lab: 1) HSC characterization in large animal models, 2) development of improved vector systems and transduction methods for HSC gene transfer, 3) analysis of integration site patterns of different retroviruses, 4) analysis of the clonal composition of hematopoiesis after transplantation of gene-modified HSCs, 5) studies of drug resistance gene therapy approaches in large animal models, 6) development of anti-HIV gene therapy strategies in the nonhuman primate SHIV model, 7) development of efficient HSC expansion strategies, 8) gene targeting and correction in HSCs, 9) ES cell studies and reprogramming in the nonhuman primate model.

We have now also 2 clinical gene therapy studies funded by the NIH. One study aims at introducing the MGMTP140K resistance gene into autologous CD34+ in patients with glioblastoma to make the hematopoietic system resistant to the myelosuppressive effects of BCNU and temozolomide chemotherapy, thus hopefully allowing the safe administration of more intensive chemotherapy and improved survival. The other clinical study aims at correcting the genetic defect in patients with Fanconi anemia.


Thalia Papayannopoulou (Hematology, Medicine)

Dr. Thalia Papayannopoulou's research program aims to understand the mechanisms whereby hematopoietic stem cells home to bone marrow following transplantation, and how they traffic between the marrow and the blood stream under normal and perturbed hematopoiesis. A particular focus is on the characterization of the hematopoietic stem cell niche. In addition, Papayannopoulou lab studies erythroid cell development during the embryonic, fetal and adult stages of development.

Robert Richard (Hematology, Medicine)

My research involves the development of virus vectors that 1) block HIV replication and 2) correct disorders of red blood cells. In addition, methods to improve engraftment of genetically modified cells are being tested. Following pre-clinical testing, my group intends to test foamy virus vectors that express anti-HIV proteins in patients with HIV-associated lymphoma.

David Russell (Medicine)

David Russell’s laboratory is studying the genetic manipulation of stem cells. In particular, viral vectors are used to both introduce genes and modify cellular genes in several types of stem cells. This includes research on genetic diseases such as brittle bone disease and acquired diseases such as AIDS that can in principle be treated with genetically modified “adult” stem cells. A major area of investigation is the genetic engineering of human embryonic stem cells. Over the last decade, Dr. Russell’s laboratory has developed a novel method for specifically changing chromosomal genes in human stem cells that is far more efficient than any other existing technique. Research is under way with human embryonic stem cells in order to make them suitable for clinical use. A major focus is to overcome the immunological barriers that prevent cultured stem cell lines from being used in transplantation. Dr. Russell is using this novel “gene targeting” approach to engineer the genes that determine whether a cell will be rejected after transplantation, in order to create patient-specific stem cells from existing stem cell lines. These cells will be matched to patients, just as bone marrow cells are matched prior to bone marrow transplantation. This strategy will overcome the need for “therapeutic cloning” in order to generate patient-specific stem cells, which is a highly controversial and extremely complex technique requiring the cloning of human embryos. Each cell line generated by Dr. Russell’s approach will be compatible with a significant percentage of the population, allowing it to be used in multiple patients to treat any disease where embryonic stem cells are being evaluated. This would overcome one of the most significant barriers to the therapeutic use of stem cell lines, and move this technology into clinical trials.

Beverly Torok-Storb (FHCRC)

Obviously FHCRC/UW lead the world in the science and medicine applied to regenerating an hematopoietic system—a Nobel was awarded for this effort. Importantly, and less obvious is the fact that the preclinical model used to develop this application (canine model) is unique to the FHCRC/UW. We have the most extensive canine facility and experience with the canine model in the world. Now we also have canine ESC, ( I believe we have the only true lines). Hence we are posed to do critical in vivo experiments in a large, outbred, long-lived animal that has proven efficacy for translation directly to humans. Moreover developmental studies using new lines and SCNT can be done in this model now with NIH funds. Non-NIH support can focus on human ESC done in parallel. But the real bonus is that derived tissue can first be tested in dogs and if proven safe, quickly translated to patients. I strongly maintain that mice being small, inbred, and short-lived provide misleading information regarding questions of long-term regeneration by allogeneic sources of cells.

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