Stem cells. -Dr Dinesh Bhurani, MD, DM, FRCPA. Rajiv Gandhi Cancer Institute, Delhi, -Director, Department of Haematology and BMT
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1 Stem cells -Dr Dinesh Bhurani, MD, DM, FRCPA -Director, Department of Haematology and BMT Rajiv Gandhi Cancer Institute, Delhi,
2 Flow of presentation Update on stem cell uses Haematopoietic stem cell transplantation Storing cord blood cells
3 Stem cell
4 Stem cells can be either totipotent, pluripotent, multipotent, or unipotent. Stem cells can be derived from human embryos or somatic tissues in the adult or they can be created by inducing greater potency in an already differentiated somatic cell.
5 Stem cells
6 Induced pluripotent stem (ips) cells Genes that were expressed in pluripotent ES cells, but not generally in mature cells, and introduced them into mature cells Reprogramming, induced a pluripotent state in a previously differentiated cell type
7
8 ips
9
10 CLINICAL APPLICATIONS Stem cells as therapy Stem cells as targets of drug therapy Stem cells to generate differentiated tissue for in vitro study of disease models for drug development
11 CLINICAL APPLICATIONS Hematopoietic stem cell transplantation Burn therapy, bone grafting, and corneal transplant tissues are examples of other current uses of stem cell generated tissue
12
13
14 Retinal disease In 2015, the first phase 1/2 study reported on the safety and tolerability of human ES cell use for the treatment of patients with retinal disease This involved nine patients with dry age-related macular degeneration and nine patients with Stargardt's macular dystrophy Human ES cell differentiation resulted in greater than 99% pure retinal pigment epithelium (RPE) Improvement in visual acuity was noted in the injected eye in 10 of 18 patients No evidence of adverse proliferation, rejection, or serious ocular or systemic safety issue
15 Other uses Parkinson disease and hemophilia A, ips cells have been generated and used to differentiate cells that could then be transplanted for therapy. Fanconi anemia Huntington disease (HD) Spinal cord injury Diabetes mellitus type I
16 Disease modifiers The ability of certain stem cells to alter disease without engrafting has been explored as a means of modifying cellular response to injury or aberrant immune activity Mesenchymal stem cells have been tested in clinical trials in humans in GVHD, and in inflammatory bowel disease
17 Drugs targeting endogenous stem cells Stem cells resident in adult tissues may be targets for pharmacologic interventions The potential of PGE2 to promote hematopoietic stem cell engraftment was tested in the setting of hematopoietic cell transplantation
18 Disease models Creating in vitro disease models that may improve molecular understanding of disease and accelerate the development of new therapies Disease modeling is in the setting of cancer
19 Challenges in the clinical use of stem cells as replacement Tissue integration : How transplanted cells will integrate into surrounding tissue to achieve a physiologically beneficial effect Oncogenesis : The potential for transplanted cells to form tumors Directed differentiation : The ability to direct the differentiation state of the cells to be used Uniformity and consistency :
20 ETHICAL CONSIDERATIONS Using embryonic stem cells Concern regarding the placement of cells in tissues highly intolerant of aberrant growth control such as the central nervous system and heart Defining the genetic integrity of manipulated cells can be extremely difficult Whether the cells have tumorigenic potential is hard to define Profusion of centers in many parts of the world, often offering treatment without clear definition of what cells would be used, what the source of cells is, and what the full experience has been
21 Gene therapy Gene therapy is one of two technologies (the other is hematopoietic cell transplantation, HCT) with the potential to cure genetic disease The gene copy must be introduced into a sufficient number of cells The gene copy also be adequately expressed for its product to correct the deficiency Genetically engineered viruses are used to carry the DNA of interest into host cells Gene therapy is complicated by technical difficulties and risks of side effects from genomic manipulation
22 Stem cells transplantation
23 Autologous bone marrow/ peripheral stem cell transplant Allogeneic bone marrow/ peripheral stem cell transplant Sibling matched transplant Matched unrelated transplant (MUD) Haplo-identical transplant
24 Autologous transplant Myeloma Non hodgkin lymphoma Hodgkin lymphoma Acute myeloid leukemia Neuroblastoma Autoimmune disorders
25 Allogenic transplantations Cancers AML ALL CML MDS Myeloproliferative ds Other disorders Thalassemia Aplastic anaemia Metabolic disorders Cong. marrow failure ds
26 HLA
27 HLA Inheritance Mother Father A 1 2 A 9 10 B C DR B C DR Child 1 Child 2 Child 3 Child 4 A 1 9 A 1 10 A 2 9 A 2 10 B 3 11 B 3 12 B 4 11 B 4 12 C 5 13 C 5 14 C 6 13 C 6 14 DR 7 15 DR 7 16 DR 8 15 DR 8 16
28 Bone marrow transplantation unit
29 Stages Pre-transplant conditioning Stem cell harvest/infusion Engraftment Post-engraftment period
30 Pre-transplant conditioning
31 Myelo-ablation Total body irradiation Gy (fractionated) + cyclophosphamide Cyclophosphamide + busulfan Nb 4.5 Gy fatal in 50% exposed individuals
32
33 Hematopoietic stem cell infusion
34 Engraftment period
35 Haematological chart in autograft Autologous PBSCT stem cells Neuts Plts Neuts Plts Chemo PBSC Days 0
36
37 Post engraftment period
38 Post engraftment complications Graft Vs Host Disease Infections Relapse Rejection Organ damage
39 Thalassemia
40
41 Aplastic anemia
42 Whether cord should be stored for future use
43 Private cord blood banking An estimated 0.04% to 0.005% chance that an individual will develop a disease treatable with their own stored cord blood by 21 years of age using a hematopoietic transplant approach
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