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ENDOCRINE > B. ISLET AND STEM CELL THERAPY > Flashcards

B. ISLET AND STEM CELL THERAPY Flashcards

1
Q

problems with T1DM insulin therapy

A

doesn’t eliminate long complications:
- retinal damage
- diabetic foot ulcers
- costly

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2
Q

what are the 3 strategies to regenerate beta-cell function

A
  1. organ transplants
  2. islet transplants
  3. stem cell therapies
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3
Q

organ transplants

A
  • rarely performed as shortage of organs/donors
  • need to be tissue compatible so no risk of rejection and in perfectly good use
  • morbidity associated with surgery as its very long
  • risks associated with long-term immune suppression (infection, malignancy, bone disease, CVD)
  • reserved for end-stage renal failure patients requiring a kidney and pancreas transplantation
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4
Q

Islet of Langerhans transplantation

A
  • isolated islet cells from donor tissue engrafted into liver (done on NHS)
  • or insulin producing beta-cells
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5
Q

what is the protocol for islet transplantation

A

The Edmonton Protocol
- collagenase in pancreas releases intact islet cells
- the islets are purified and injected through a percutaneous catheter into portal vein of liver
- can produce insulin

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6
Q

what is required for the islet transplantation

A
  • islet cells purified from donor organ
  • perfused into liver under local anaesthetic
  • immunosuppression required: 5 doses of Daclizumab at 1mg/kg IV over 8 weeks followed by maintenance on Tacrolimus
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7
Q

what was the outcome of the Edmonton protocol

A
  • initially poor success rates
  • clinical trial primary end-point defined as insulin independence at 1 year
  • 44% of patients met primary endpoint
  • 76% required insulin therapy within 2
    years
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8
Q

when and for who are islet transplants performed

A
  • available on NHS since 2008 but only 152 procedures from 2008-2015
  • sometimes offered to T1DM patients who suffer regular hypos
  • they often have poor hypoglycaemic awareness (will have seizures and collapse)
  • more likely in patients on long-term insulin treatment
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9
Q

benefits of islet transplants

A
  • reduced frequency of hypos
  • improved awareness of hypo symptoms
  • normally functional for 6-10 years
  • patients continue to need low dose insulin therapy
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10
Q

who is islet transplants not suitable for

A
  • weight>85kg
  • poor kidney function
  • requires >50 units insulin daily
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11
Q

risks of islet transplants

A
  • infection from procedure
  • small increased cancer risk
  • rejection of transplant
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12
Q

what are the three main types of stem cells

A
  1. embryonic stem cells (pluripotent)
  2. adult stem cells (multipotent)
  3. induced pluripotent stem cells
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13
Q

what are pluripotent stem cells

A
  • cells that divide (self-renew) indefinitely and can potentially differentiate into the 3 primary germ layers (ie: endoderm, mesoderm, ectoderm) and hence all other cell types in body
  • no lifespan
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14
Q

what are pluripotent stem cells currently used for

A
  • cornea regeneration
  • skin repair
  • bone repair etc
  • bone marrow blood cells
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15
Q

embryonic stem cells

A
  • pluripotent: can form all cells of body
  • self-renewal or differentiation
  • expression of specific gene networks (response to environmental signals) determines self-renewal (stem-cell) or differentiation
  • there are certain TFs in stem cells which can activate stem cell genes to keep it as a stem cell
  • when it differentiates, those TFs are suppressed and others come in and activate differentiated cell gene expression programmes
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16
Q

what is the source of ESCs

A
  • patients undergoing IVF treatment
  • Surplus IVF embryos (blastocytes) donated with consent to hospital
  • inner mass cells removed before destruction
  • cultured ESCs for research, clinical applications
17
Q

adult stem cells

A
  • multipotent: can generate certain types of cells
  • bone marrow, intestine, brain, fat tissues contain adult stem cells
  • they regenerate the cells of that tissue (committed progenitors)
  • can undergo self-renewal, commitment and differentiation
18
Q

what is reversing differentiation

A
  • induction of PSC from ie: mouse embryonic and adult fibroblast cultures
  • need defined factors
  • ie: skin cell to stem cell
19
Q

induced pluripotent stem cells

A
  • cultured fibroblast can be reprogrammed to become iPSC then differentiation occurs (particular tissue patient needs?)
  • come from patient
  • pluripotent associated factors: Oct4, Sox2, cMyc, Klf4, Nanog (stem cell specific TFs) - switch off all differentiated gene programs and switch on stem cell programs
  • culture conditions adjusted to generate different cell types
  • challenges: low efficiency, controlling differentiation
20
Q

disadvantages of human ESCs

A
  • not human matched
  • immunosuppression may be needed
  • ethical concerns? (objection to using embryo tissue)
21
Q

advantages of iPSCs

A
  • resemble ESCs
  • genetically identical to patient
  • amenable to genome editing - correcting genetic defects (then put back in patient)
22
Q

disadvantages of iPSCs

A
  • may have incomplete reprogramming (experimental technique)
23
Q

are iPSCs a ideal cell therapy for islet regeneration

A
  • IPSCs from patient are grown in lab
  • differentiation into beta-cells (or other cells of islet)
  • engraft into patient’s liver via Edmonton Protocol via perfusion technique
  • stem cells stored for future rounds of islet regeneration (-80 degrees Celsius or under liquid N)
  • autoantibodies still attack stem cells (beta-cells)
  • give another transfusion in 5 years
24
Q

future prospects and challenges with stem therapy

A
  • preclinical trials are very promising for hES and IPS cells as insulin producing beta cells produced in vivo
  • unclear which strategy will be most effective in the clinic
  • underlying autoimmune disease will still be present so likely to require repeated administration (1 dose per year)
  • beta-cells encapsulated within devices can be implanted in the body but can induce fibrotic immune reaction
  • novel (ie - clotting) less immunogenic materials may improve these devices
  • genome editing (CRISPR CAS9 technology) might be used to protect the encapsulated cells from immune system
25
Q

what is CRISPR CAS9

A
  • genome editing tool
  • molecular scissors (enzyme) which is guided into DNA and knows which specific gene sequence to cut by guide RNA
  • guide RNA = copy of sequence want to cut (20 bp)
  • CRISPR CAS9 is suitable for adenovirus vector delivery
26
Q

applications of CRISPR CAS9

A
  • gene (base) editing: allele specific
  • corrections of mutations
  • enhance or suppress specific gene expression
27
Q

macro-encapsulated beta-cells

A
  • vascularised pouch with beta-cells in it
  • wear inside or outside body
  • develop blood capillary system
  • can sense blood glucose and produce insulin
  • overcomes need for injections
28
Q

micro-encapsulated beta-cells

A
  • porous barrier to immune cells
  • beta-cells in capsules so antibodies can’t attack them
29
Q

‘super beta-cells’

A
  • CRISPR gene edited “Super beta-cells” (could it cause cancer)
  • not recognised by immune cells (resistant to autoantibodies)
  • inbuilt suicide mechanism to eradicate if needed (cells will die if become tumorous etc)

ENDOCRINE (17 decks)

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