Stem Cell Research:
From Bench Side To Bed
Side
Prof : Heba M Saad Eldien
Professor Of Histology And Cell Biology College Of Medicine- Jouf University
Former :Manager Of Tissue Culture And Molecular Biology Center(Stem Cell Unit)
Faculty Of Medicine -Assiut University
Agenda
Background
potential and the limitations of stem cells
History of Clinical trials
how and when to begin trial treatments in humans?
if the trials are successful how to make such
treatments fairly available.??
Are stem cells currently used in therapies today?
What are the obstacles that must be overcome before the potential uses of stem cells in cell therapy will be realized?
Where Are We Now??
Stem Cell – Definition A cell that has the ability to:
• self-renew (divide in a way that generates more stem cells)
• differentiate (to turn into mature,
specialized cells that make up our
tissues and organs).
Kinds of Stem Cells
Stem cell
type Description Examples
Totipotent Each cell can develop into a new individual
Cells from early (1-3 days)
embryos
Pluripotent
Cells can form any (over 200) cell types
Embryonic stem cells&induced
pluripotent stem cells or iPS cells
Some cells of blastocyst (5 to 14 days)
Multipotent
can form a number of other tissues
‘Tissue-specific’ or
‘adult’ stem cells
Fetal tissue, cord blood, and adult stem cells
Types of Adult Stem Cells
• Hematopoietic
• Mammary
• Mesenchymal
• Neural
• Endothelial
• Olfactory
• Neural crest
• Testicular
Stem cells hold the incredible regenerative potential to treat currently untreatable diseases, such as age-related ), macular degeneration (AMD Stem cell therapies also have practical applications in treating blood-based illnesses, such as acute myeloid leukemia
and HIV infections.
Why Stem Cell??
Stem cell Transplantation:
Current Indications
• Hematologic Malignancies
• Solid Tumor Malignancy
• Hereditary Disorders
• Immune Deficiency Syndromes
• Genetic Disorder
sMSC clinical trials-
Non- Heme disease applications
• MI
• Cardiomyopathy
• Inflammatory bowel disease
• Diabetes mellitis
• Endstage Liver Disease
• Multiple sclerosis
• Vascular disease: CVA, PVD
• Spinal cord injury
• ALS
Stem Cells for Heart disease
Stem Cell Tx Futures:
Cardiac Disease?
• Transplanted hematopoietic stem cells (HSC) repair myocardial infarcts, Orlic et al., Nature, 2001
• Rationale:
Human studies:
• 1997: 1.1 million MIs; 800,000 revascularization procedures
• 2001- first cell therapy intervention for CHF
• 2003- intracardiac skeletal myoblast injections, Smits, J Am Coll Cardio
• 2004- auto BMC cath delivered coronary artery infusion with improved LVEF (n=60), Wollert, Lancet
• 2007- Zenovich reported 5 yrs of collective experience> 1000 pts generally safe but some concerns exist; mixed results in clinical studies, Exp Pharm
• 2009- randomized trials emerge with mixed endpoints
Possible Explanations for Improved Cardiac Function after Administration of Bone Marrow–
Derived Cells, Keating, 2007
Neovascularization
Paracrine effect: cytokine/chemokine release
Extracellular matrix remodeling
Recruitment of endogenous stem cells
Engraftment/differentiation/cell
fusion of administered cells
Lung disease
• Pulmonary hypertension
• ALI
• COPD
• Bronchiolitis
• Reduced systemic and pulmonary cytokines
• Prevented ALI and organ dysfunction
• Down-regulation of inflammation and
inflammation-related genes (IL-10, IL-6)
• Up-regulation of genes involved in phagocytosis
• Improved bacterial clearance by enhanced phagocytic activity
• In multiple clinical trials currently
MSC therapy
Improved survival
AMS50
Graft >d50 after spleen cell application from
“tolerant“
animal- MSC exposure
MSC as immune suppressive agent Heterotopic Heart Transplant
Allogeneic heart is grafted to adominal artery
and venous circulation – keeps on beating
Regenerative Medicine
• Process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects
• It helps to produce extended
healthy longevity,
Potential of Adult Stem Cells
Treating Leukemia
• Leukemia results when white blood cells made in bone marrow begin to grow and function abnormally
• One way to do this is through chemotherapy
• When chemotherapy cannot solve the problem, doctors turn to bone marrow transplants.
Another Stem Cell Victory - Parkinson's Disease
• A degenerative disorder of the central nervous system
• Sufferers lack a sufficient amount of a brain chemical called dopamine
• The cure of this disease is to multiply cells that release dopamine
Insulin Independence
• There is insulin independence for Type 1 diabetes patients
• A study showed patients receiving injections with adult stem cells were able to go as long as four years without having to rely on insulin shots.
Heeling of Heart by Adult Stem Cells
Cardiologists and heart • surgeons worldwide currently use VesCell™
adult stem cell therapy to treat patients suffering artery coronary
from
cardiomyopathy, disease,
heart congestive
and
. failure
Process of stem cells for spinal cord injury
• Bone Marrow taken from the hip 6 weeks of cultivating the adult stem cells to increase total to 100 million.
• Adult Stem Cells
injected at injury site
(C3-C4) in a surgical
procedure
Thalesemia
• The genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin
• Hematopoietic stem cell transplantation (HSCT) is the only curative approach
Curing cancer
• Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics
associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample
• Lisa Ray to undergo stem cell transplant for blood cancer
Benefits of Adult Stem Cell Research
• Easy to obtain
• Potentially limitless in supply
• Patients can use their own stem cells for treatment and therapy
• Adult stem cells are politically neutral
• Not offensive to any major interest group nor do they generate controversy.
Limitations of adult stem cell
• Patient's brain, would be impractical
• Genetic disorder
• Maintenance in culture is difficult
• Very difficult to grow and to expand in the laboratory.
• Mode of administration
• Many are unproven!!!!!!, and very expensive.
The future of cell therapy
30
Tracheal Replacement, Macchiarini , Lancet 2011
Autologous BM derived MSC expanded in bioreactor and cocultured with scaffold; 3D
imaging to
reconstruct model of trachea;
implanted in 33 yo s/p resection of tracheal cancer
Organ regeneration
Decellularized organs
Recellularized liver with in vivo function after heterotopic implantation,
Uygun, Nature Med, 2010
History of Clinical trials
The first clinical trial using culture-expanded • MSCs 1995 and 15 patients were was performed in
treated with autologous stem cells
. After the first one, a number of clinical trials • have been conducted to test the feasibility and efficacy of MSCs therapy. From 2011, 206
clinical trials using MSCs were published on the public clinical trials database
) gave wide range http://www.clinicaltrials.gov/
( of therapeutic applications.
Phase I studies, Phase • Most of these trials are
. II, and a combination of Phase I/II studies
Clinical trials
• Only a small number of these trials are in Phase III or Phase II /III. Most of the trials reported lack of adverse effects in the medium timing, although few of them showed mild and transient peri-injection effects:
• in general, MSCs seem to be
well tolerated [. Very promising results
were obtained by the injection of
autologous and allogenic MSCs in
patients suffering from osteogenesis
imperfecta
What are the obstacles that must be overcome before the potential uses of stem cells in cell
therapy will be realized?
Autologous vs allogeneic
Universal donor or donor directed
MSC : bone marrow vs adipose vs placenta
HSC : cord vs bone marrow vs PBSC
Selected?
Activated?
Fresh vs cryopreserved?
IPS
• Maximal tolerated dose (MTD) has not identified in most if not all studies
• Maximal deliverable dose (MDD) may be more relevant endpoint !!!!!
• No understanding of clearance of cells or biodistribution
• No potency determination
• Personalized product genetic variants
Reflections: What have we learned?
About FDA-approved products derived from stem cells
The only stem cell-based
products that are FDA-approved for use in the United States
consist of blood-forming stem cells (hematopoietic progenitor cells)
derived from cord blood.
In May 2018 Mayo Clinic’s Center for
Regenerative Medicine have developed an FDA-approved automated bioreactor. The
billions of stem bioreactor can manufacture
cells within a short period, producing in a matter of days
They now can develop phase II trials enrolling larger numbers of
patients
touting crack down on stem cell clinics
After
unapproved therapies, the FDA agency now
plans to help the development of stem cell
therapies proved to be safe and effective
The newest FDA guidelines (2018) state that “stem cell-derived products that are minimally altered and are used for the same purpose in both do not need donor and host
and are subject premarket approval
only to regulations that prevent the transmission of communicable
diseases.”
As the gaps between new stem cell therapies and regulatory bodies are
bridged,
that new and Global Data expects
exciting therapeutic options will and their become available
subsequent markets will open.
Where Are Now
GTCbio Stem Cell Research &
Regenerative Medicines
Conference, which is part of the larger Stem Cell Summit 2016
(April 25-27, 2016 in Boston Ma – USA )!
Role of Autologus bone marrow derived hepatocyte like cells in decompensated liver
chirrosis
6 - 1 - 2008 60
UK NEQAS for
Molecular Genetics www.ukneqas-
molgen.org.uk
Director: Dr Sandi
Deans Department of Laboratory Medicine The Royal Infirmary of Edinburgh 51 Little
France Crescent
Edinburgh EH16 4SA United Kingdom
Scheme email:
Mission
.
Fulfillment accreditation procedures.
Excellence in our research, dynamic
partnerships between our laboratories and clinics.
Outstanding education and training programs for future scientists and clinicians in area of stem cell therapy and tissue engineering
. Becoming a reference center for cancer prediction and personalization
Vision:
Application of stem cell therapy while providing the highest level of safe and innovative therapy
Translation of discoveries into innovative
clinical applications (i.e., clinical regenerative medicine research)
solving the problems of anti cancers
resistance, application of immunotherapy
Team Work in TC&MB
Greeting at TC &MB lab (Stem Cell Unit-
Assiut University )
68
http://www.aun.edu.eg/faculty-
medicine/tc&mb/index.html
References
ENSAF M. AL-HUJAILY1**, et al.,
BIOMEDICAL REPORTS 8: 275-282, 2018 Abstract. The
Therapeutics discovery: From bench to first in-human trials*
Mohamed H. Abumaree , 1,2et al., 2014 Stem Cell Research and Regenerative
Medicine at King Abdullah International Medical Research Center
Hundreds of clinics in US offering stem cell therapies without FDA approval Ophthalmology, July 22, 2018.
SPECIAL REPORT
Balancing Safety and Innovation for Cell-Based Regenerative Medicine Peter Marks, M.D., Ph.D.,
and Scott Gottlieb, M.D.NEW England Journal Of Medicine 2018
