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Stem Cell Therapies

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					  Genomics, Bioinformatics & Medicine
              http://biochem158.stanford.edu/


               Stem Cell Therapies
http://biochem158.stanford.edu/Stem%20Cell%20Therapies.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 iPSCs
•   Spinal Cord Injury with human embryonic stem cells (hESCs)
•   Sickle Cell, Thalassemias, hemophilia and other blood diseases with
    iPSCs
•   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




                                  - Gero
                     Tom Okarma Brutlag 2011
                             Doug
Human Embryonic Stem Cells




                                    - Gero
                       Tom Okarma Brutlag 2011
                               Doug
  Spinal Cord Injury
Pathology at the Lesion




                                   - Gero
                      Tom Okarma Brutlag 2011
                              Doug
GRNOPC1 Improves Locomotor Behavior
      after Spinal Cord Injury




                                       - Gero
                          Tom Okarma Brutlag 2011
                                  Doug
      Spinal Cord Injury
http://www.geron.com/GRNOPC1Trial/




                                     Doug Brutlag 2011
GRNOPC1 Induces Remyelination after
  Spinal Cord Lesions in Rodents




                                        - Gero
                           Tom Okarma Brutlag 2011
                                   Doug
GRNOPC1 Promotes Neural Outgrowth




                                      - Gero
                         Tom Okarma Brutlag 2011
                                 Doug
Human Embryonic Stem Cell (hESC)
        Based Therapy




                                      - Gero
                         Tom Okarma Brutlag 2011
                                 Doug
Geron Oligodendrocyte Progenitor Cells
             GRNOPC1




                                          - Gero
                             Tom Okarma Brutlag 2011
                                     Doug
Properties of GRNOP1




                                - Gero
                   Tom Okarma Brutlag 2011
                           Doug
GRNOP1 Phase 1 Multi-Center
   Spinal Cord Injury Trial




                                   - Gero
                      Tom Okarma Brutlag 2011
                              Doug
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_stemPathway.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

                           Health
                             y
                           Donor




             Purify from
             Tumor cells


                                           Unfractionated bone
                                           marrow or mobilized
                                           blood
Transplant                                      Transplant


                                            Donor blood
                                            formation, graft-vs-
                                            tumor effect


                                                    Shizuru
                                             JudithDoug 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_stemPathway.asp




                                               Doug Brutlag 2011
                Hematopoietic Idiotype Markers




Weisman and Shizuru (2008) BLOOD112, Pages 3543-3553, 2008.   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

        MOG




                                    Judith Shizuru
                                          Doug Brutlag 2011
                 Partial Chimerism Results in
                    Disease Amelioration
5
5

4
          TBI                        TLI + ATS
4
3

2
3
1

2
0


1

0
    -35                     +60                               +60
                                  TLI + ATG
                                              HSC
          TBI & HSC




                                                    Judith Shizuru
                                                         Doug 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



                    80                                           NOD male controls
Diabetes free (%)




                                                                 NOD female controls
                                                                 NOD WBM          NOD
                    60
                                                                 NOD HSC       NOD
                                                                 AKR HSC         NOD
                    40



                    20            txp

                     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
                                                        Transplan
               Müller et al. (2011) Biol. Blood Marrow Doug Brutlag 2011

				
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