Genomics Bioinformatics Medicine http biochem 158 stanford edu
Genomics, Bioinformatics & Medicine http: //biochem 158. stanford. edu/ Stem Cell Therapies http: //biochem 158. stanford. edu/Stem%20 Cell%20 Therapies. html Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine Doug Brutlag 2011
Stem Cell Promise & Stem Cell Therapeutics http: //www. stemcelltherapies. org/ • • Parkinson’s Disease with i. PSCs Spinal Cord Injury with human embryonic stem cells (h. ESCs) Sickle Cell, Thalassemias, hemophilia and other blood diseases with i. PSCs Bone Marrow Transplants (BMT) & hematopoietic stem cell therapy (HCT) – Lymphomas and thymomas – Hematopoietic cells – Metastatic cancers of other origins • Autoimmune Diseases with hematopoietic stem cells (HSCs) – – – Rheumatoid arthritis Systemic Lupus Erythematosus Type 1 diabetes mellitus Multiple sclerosis Pernicious anemia Doug Brutlag 2011
Geron Stem Cell Therapy Tom Okarma - Geron Doug Brutlag 2011
Human Embryonic Stem Cells Tom Okarma - Geron Doug Brutlag 2011
Spinal Cord Injury Pathology at the Lesion Tom Okarma - Geron Doug Brutlag 2011
GRNOPC 1 Improves Locomotor Behavior after Spinal Cord Injury Tom Okarma - Geron Doug Brutlag 2011
Spinal Cord Injury http: //www. geron. com/GRNOPC 1 Trial/ Doug Brutlag 2011
GRNOPC 1 Induces Remyelination after Spinal Cord Lesions in Rodents Tom Okarma - Geron Doug Brutlag 2011
GRNOPC 1 Promotes Neural Outgrowth Tom Okarma - Geron Doug Brutlag 2011
Human Embryonic Stem Cell (h. ESC) Based Therapy Tom Okarma - Geron Doug Brutlag 2011
Geron Oligodendrocyte Progenitor Cells GRNOPC 1 Tom Okarma - Geron Doug Brutlag 2011
GRNOP 1 Phase 1 Multi-Center Spinal Cord Injury Trial Tom Okarma - Geron Doug Brutlag 2011
Clinical Trials Database http: //clinicaltrials. gov/ Doug Brutlag 2011
Stem Cell Clinical Trials http: //clinicaltrials. gov/ Doug Brutlag 2011
Geron Clinical Trials http: //clinicaltrials. gov/ Doug Brutlag 2011
Clinical Trials of Hematopoietic Cell Transplantation Judith A. Shizuru, M. D. , Ph. D. Division of Blood and Marrow Transplantation Stanford University Medical Center Judith Shizuru Doug Brutlag 2011
Hematopoiesis http: //www. biocarta. com/pathfiles/h_stem. Pathway. asp Doug Brutlag 2011
Bone Marrow Transplants to Cure Lymphomas/Thymomas • Whole Body Irradiation to remove endogenous immune system and tumor – Also total lymphoid irradiation with antithymocyte serum • Injection of bone marrow from a well matched donor to re -establish immune system • Regulation of immune response to prevent graft versus host reaction. • Autologous donation possible if one can purify and remove tumor cells, enriching for stem cells. . • Allogeneic donors have advantage of graft versus tumor reaction to kill any remaining tumor cells. • Allogeneic donors have the disadvantage of graft versus host reaction if they are not well matched. Judith Shizuru Doug Brutlag 2011
Autologous vs. Allogeneic Transplants Autologous Allogenic Healthy Donor Purify from Tumor cells Unfractionated bone marrow or mobilized blood Transplant Donor blood formation, graft-vs-tumor effect Judith Doug Shizuru Brutlag 2011
Complications of Allogeneic Transplants Transplant related mortality = 10 - 15% • Regimen related toxicity • Infectious complications • Engraftment failure (resistance) • Graft-versus-host disease Judith Shizuru Doug Brutlag 2011
Judith Shizuru Doug Brutlag 2011
Cells of the Bone Marrow Judith Shizuru Doug Brutlag 2011
Regulation of hematopoiesis by cytokines http: //www. biocarta. com/pathfiles/h_stem. Pathway. asp Doug Brutlag 2011
Isolation of Hematopoietic Stem Cells Judith Shizuru Doug Brutlag 2011
Fluorescent Activated Cell Sorter (FACS) Herzenberg & Herzenberg http: //www. bio. davidson. edu/courses/genomics/method/FACS. html Doug Brutlag 2011
Why Transplant Purified Allogeneic HSCs? Judith Shizuru Doug Brutlag 2011
Engraftment Resistance is Significant Obstacle to HSC Transplantation Judith Shizuru Doug Brutlag 2011
Experimental Autoimmune Encephalomyelitis (EAE) Model for Multiple Sclerosis in Mice MOG MOG Judith Shizuru Doug Brutlag 2011
Partial Chimerism Results in Disease Amelioration 5 4 3 2 5 TLI + ATS TBI 4 3 1 0 2 1 0 +60 -35 TBI & HSC +60 TLI + ATG HSC Judith. Doug Shizuru Brutlag 2011
Other Applications of Hematopoietic Stem Cell Transplantation • Treatment of autoimmune disease – Patients treated with bone marrow transplants are often cured of autoimmune disease – Bone marrow transplant donors with autoimmune disease can pass the disease on to recipients • Organ tolerance induction – Mice receiving organ transplant and HSC transplant together are tolerant and no rejection occurs. No immune suppressants are needed. Judith Shizuru Doug Brutlag 2011
Combined HSC & islet transplantation Judith Shizuru Doug Brutlag 2011
Treatment of Diabetic Mice (NOD) with Hematopoietic Stem Cell Transplants 100 NOD male controls NOD female controls Diabetes free (%) 80 NOD WBM 60 NOD HSC AKR HSC NOD NOD 40 txp 20 0 0 2 4 6 8 10 12 14 Months after birth Judith Shizuru Doug Brutlag 2011
Hematopoietic Cell Treatment Coupled with High Dose Breast Cancer Chemotherapy Stage Four Metastatic Breast Cancer Müller et al. (2011) Biol. Blood Marrow Transplant Doug Brutlag 2011
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