Transcript Stem Cell Therapies

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/
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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
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Autoimmune Diseases with hematopoietic stem cells (HSCs)
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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
GRNOPC1 Improves Locomotor Behavior
after Spinal Cord Injury
Tom Okarma
- Geron
Doug Brutlag 2011
Spinal Cord Injury
http://www.geron.com/GRNOPC1Trial/
Doug Brutlag 2011
GRNOPC1 Induces Remyelination after
Spinal Cord Lesions in Rodents
Tom Okarma
- Geron
Doug Brutlag 2011
GRNOPC1 Promotes Neural Outgrowth
Tom Okarma
- Geron
Doug Brutlag 2011
Human Embryonic Stem Cell (hESC)
Based Therapy
Tom Okarma
- Geron
Doug Brutlag 2011
Geron Oligodendrocyte Progenitor Cells
GRNOPC1
Tom Okarma
- Geron
Doug Brutlag 2011
GRNOP1 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_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
Healthy
Donor
Purify from
Tumor cells
Unfractionated bone
marrow or mobilized blood
Transplant
Transplant
Donor blood formation,
graft-vs-tumor effect
Judith Doug
Shizuru
Brutlag 2011
Complications of Allogeneic Transplants
Transplant related mortality = 10 - 15%
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Regimen related toxicity
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Infectious complications
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Engraftment failure (resistance)
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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
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
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TLI + ATS
TBI
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1
0
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1
0
+60
-35
+60
TLI + ATG
HSC
TBI & HSC
T cells
1 .0 0
B cells
Macrop ha ges
0 .7 5
Gr anulocytes
0 .5 0
0 .2 5
0 .0 0
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T ime ( d ays )
JudithDoug
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
NOD
40
txp
20
0
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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