Transcript Whole Pancreas Transplants

Stem Cells and Diabetes:
A Website for BI108
David Keyzer
Nicholas Marcantonio
Lesley Rabach
Morgan Rabach
Sannon Watkins
Diabetes
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Diabetes is a syndrome
characterized by
hyperglycemia and
glucose intolerance.
This is due to either
insulin deficiency or
impaired effectiveness of
insulin action.
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There are two main classes of
diabetes
Class I-”juevenile diabetes”,
arises due to autoimmune
destruction of pancreatic beta
cells that secrete insulin
Class II-”adult onset
diabetes”, arises due to
insufficient insulin production.
Symptoms can often be
controlled by exercise and
dietary restriction.
Stem cell therapies hold
promise for the treatment of
both classes.
Significant Risks are associated
with Diabetes
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Heart disease/High blood
pressure
-Diabetics die from heart
disease 2 to 4 times as often
as diabetes free adults.
-60% to 65% of people with
diabetes have high blood
pressure
Stroke
-The risk of stroke is 2 to 4 X
higher in diabetic people.
Blindness
-Diabetes is the leading
cause of new blindness in
adults ages 20 to 74.
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Kidney disease
-Diabetes is the leading
cause of end-stage renal
disease (ESRD). It accounts
for ~ 40% of new cases.
-In 1995, approximately
100,000 diabetic people
underwent dialysis or kidney
transplantation.
Amputations
- More than 50% of lower limb
amputations in the United
States result from diabetes
related problems.
Diabetes Impact on Society
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About 16 million people (5.9%
of the population) in the
United States have diabetes
mellitus.
Diabetes is one of the leading
causes of death and disability.
It was listed as the 7th leading
cause of death in the US by
the CDC in 1996.
Diabetes costs about $98
billion per year [1].
The incidence of diabetes is
rapidly on the rise
Source: Journal of the American
Medical Association
Economics
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Of the $98.2 Billion Spent, $52.4 Billion Were Spent on
Complications of Diabetes. This Accounts for Over 5%
of the US Healthcare Budget.
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The Average Cost of Treating Diabetes in the United
States is $3,400 per Patient per Year
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$170,000 After 50 years
Am I Covered?
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Most States Require
That Insurance
Companies Cover
Diabetes Treatment to
Some Degree
The Patient Still
Shoulders A Significant
Burden, Often Paying A
Percentage
Current TreatmentStem Cells and
the FUTURE
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Dietary adjustments and
exercise is sufficient therapy
for milder symptoms
Insulin Therapy is the most
popular current treatment for
diabetes
It is an insufficient therapy. It
does not allow for effective
adaptation to changing levels
of blood glucose
It is an inconvenience. It
requires frequent injections/
the presence of a pump
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Stem cell therapies, if
successful, offer a better
life for diabetes sufferers
No need for multiple
injections and pumps
More responsive to
changing blood glucose
levels
Stem Cells-Potential Therapy for
Diabetes
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Cells that have the capacity to
regenerate themselves for
long periods of time, and
differentiate into specific
tissues
Two main sources of stem
cells
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Adult-from adult tissues
Embryonic- from early
embryos
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Have the potential to treat
diabetes and many other
diseases(detail coming later)
However, complications
include:
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Maintaining in cell lines in
culture
Immune rejection
Teratoma formation (ES)
Difficulties in identifying and
isolating, scarcity (Adult SC)
Ethical Issues (ES)
Whole Pancreas Transplants
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1,300 people with type 1 diabetes receive whole-organ
pancreas transplants each year
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83 percent of these patients have no symptoms of diabetes
and do not have to take insulin to maintain normal glucose
concentrations in the blood. [2]
However, two obstacles prevent transplantation from
becoming a wide-spread therapy for type 1 diabetes
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Shortage of donor supply
Need for Immunosuppressive therapy
Islet Cell Transplantation
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Potential alternative for
whole-organ transplants
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Non-invasive
Less expensive
Less morbidity
Enticing, because, if islets
can be cultured and
replicated in vitro, the donor
supply can be greatly
increased
But, similar to whole-organ
transplants in that
immunosuppression would
still be needed
Source:
http://cellbio.utmb.edu/microanat
omy/Endocrines/endocrines.htm
Edmonton Protocol
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"Less than 10% of the almost 300 islet allografts
transplanted since 1990 resulted in insulin
independence for periods of more than 12 months" [3].
But in 2000, researchers reported a series of
successful transplants according to the “Edmonton
protocol” [4]
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No cyclosporine, azathioprine, or steroids
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Instead, sirolimus, tacrolimus, and daclizumab
About twice as many islets transplanted as compared to earlier
protocols
Results of Edmonton Protocol
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“All patients have been resolved
of unstable type 1 diabetes and
now have no problems with wide
swings of blood glucose or
hypoglycemia [5]
Problems include:
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Lowered white cell count
Hemorrhage
Immunosuppression
SHORTAGE OF DONOR
CELLS!!!
Long term effects need to be
evaluated, but, demonstrates that
islets can be transplanted such
that they maintain sensitivity to
glucose, and continue to secrete
insulin
Source: [4]
The Promise of Stem Cells
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Edmonton protocol shows that cell-based therapies
may serve as viable alternative to whole-organ
transplant.
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But, for cell-based therapies to become clinically
applicable
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And, in the longer term, perhaps insulin therapy
Donor supply needs to be increased
Issues regarding immunosuppression must be resolved
Stem cells offer the best way to tackle these issues
Cell Populations
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It is currently unclear whether
treatment would be beneficial
with just beta cells or with
complete pancreatic islets
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Islets contain alpha, beta, and
delta cells
Current research indicates that
beta cells are less responsive to
changes in glucose concentration
than complete pancreatic islets.
Many researchers believe that a
system in which the stem cells
will become complete islet cluster
will prove most beneficial.
Increasing Donor Supply?
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Fetal Tissue
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Already differentiated
No need for upstream specification
However:
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Small donor supply, ethical issues, difficult to culture
Adult Tissue
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Harvested from cadavers, cells lining pancreatic ducts, cells in pancreatic
tissue
Isolated patient-specific
No ethical concerns
Greater tissue supply
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But, difficulty with proliferating and culturing already differentiated beta cells from all
cadaver/live patient tissue
Increasing Donor Supply II
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Embryonic Stem Cells
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Multipotent
Limitless capacity to replicate
Easiest to genetically manipulate
Embryoid bodies contain a
subset of cells that function like
beta cells.
Implantation may lead to
teratoma formation
But, ethical concerns.
Source:
http://www.time.com/time/2001/stemcells/#
Graft Rejection/Immunology
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Ultimate goal: create a line of donor cells that can be
transplanted to diabetic patients that will not be
destroyed by a recipient’s immune system
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Thus, patients would not require immunosuppressive drugs
But, these cells must evade rejection for being nonself, as well as autoimmune antibodies
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Research has shown that patients who receive pancreas
transplants generate anti-islet antibodies to allogeneic islet
cells
Graft Rejection/Immunology 2
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Immunoisolation
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Encapsulation must:
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Problems caused by
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allow uptake oxygen and
other nutrients
allow bi-directional flow of
glucose and insulin
Biocompatible [6].
Difficult diffusion kinetics
Issues with mechanical
stability
Genetic Engineering?
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Removing/Matching HLA
antigens
Automimmunity?
Source: [7]
A Word On Ethics
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Patients Urge Research
Potentiality
What Constitutes A Person?
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Government Funding
Limited
President Limits Research on
Embryonic Stem Cells
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Past Precedents
Where to Draw the Line?
Source:
http://www.specialchildren.about.com/library/
weekly/aa073101b.htm
Interview with a Type I Diabetic
Insurance Case Example
Covers Part of the Insulin Pump Cost
$700 Deductible, then 80% of Treatment Cost
-----------------------------------------------------------------Given that a cure for diabetes were offered which entailed
some level of risk, what level of risk would you consider
acceptable?
“I would be willing to take almost no risk. Studies
Type I Diabetic
Age 21
Diagnosed 9
Years Ago
have shown a very strong correlation between
control of blood glucose and the incidence of
complications. Because I control my diabetes
very tightly, I am not at risk of any
complications, at least not for a long time. “
Interview (continued)
If a cure could be offered with little to no risk, what would you be willing to
pay?
“Well, I would have to think about the cumulative cost of my disease over my
lifetime, as well as the punitive effects of having it. It's hard to say. At this
stage of my life, this is a disease that I can live with, even though it's a
hassle.”
...
“The sentiment in the diabetes community is that a cure could almost come
any day now. With all of the diabetics I know, the feeling is positive.”
Bradley Naylor, Brown ’03
Future Outlook
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Ultimate goal
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Unlimited supply of insulin-secreting cells that will not be destroyed
via alloreactivity or auto-antibodies
In the meantime, expect stem cell research to lead to supply of
donor cells that can be used in cell-based therapies
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1st Gen: Islet transplantation with immunosuppressive drugs as
replacement for whole-organ transplants, but not insulin therapy
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2nd Gen?: Encapsulated islets that do not require
immunosuppressive drugs?
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Improved drugs(tolerance inducing drugs) may increase number of
recipients
If this is viable, perhaps it will begin to replace insulin therapy
Type II Diabetes
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New evidence suggests transplantation has benefits
Acknowledgements
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Sincere thanks to Dr. E Ed Baetge, Ph.D., the
Chief Scientific Officer of CyThera Inc. His
knowledge, insight, and experience made our
website possible. Please take some time to
visit www.cytheraco.com to learn about
CyThera, and it's research of stem cells for use
in the treatment of type 1 diabetes.
Works Cited
[1] http://www.cdc.gov/diabetes/pubs/facts98.htm#top
[2] National Institutes of Health (US) [NIH]. Stem Cells: Scientific Progress and Future Research
Directions. Bethesda (MD): NIH; 2001 Jun. Available from:
http://www.nih.gov/news/stemcell/scireport.htm.
[3] Berná G, León-Quinto T, Enseñat-Waser R, Montanya E, Martín F, Soria B. Stem cells and
diabetes. Biomedicine and Pharmacotherapy 2001;55:206-12.
[4] Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte
RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoidfree immunosuppressive regimen. The New England Journal of Medicine 2000;343(4):230-8.
[5] Ryan EA, Lakey JRT, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet
transplantation with the Edmonton protocol. Diabetes 2001;50:710-9.
[6] Berney T, Ricordi C. Islet cell transplantation: the future? Langenbeck's Archive of Surgery
2000;385:373-8.
[7] Lembert N, Petersen P, Wesche J, et al. In vitro test of new biomaterials for the development of
a bioartificial pancreas. Annals of the New York Academy of Sciences 2001;944:271-6.