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Neurophysiology > Lecture 14- Stem Cell Therapies for Parkinson's disease > Flashcards

Lecture 14- Stem Cell Therapies for Parkinson's disease Flashcards

1
Q

What is parkinson’s?

A

-Progressive degeneration of midbrain dopamine neurons

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2
Q

What is the target with stem cell therapies for Parkinson’s?

A

-getting the right type of dopamine neuron in, not just a generic one, should be the motor one

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3
Q

What are the current Parkinson’s treatments?

A
  • pharmacological treatments: L-DOPA
  • L Dopa is the main one (pre cursor to dopamine, used as it can cross the blood brain barrier)
  • number of problems= patients very responsive in the first 5 to 10 years and then efficacy decreases, the graph shows the motor responses of a parkinson’s disease
  • the extremes= too much dopamine= too much movement, little dopamine and little movement
  • excessive movement when high dopamine
  • this depends on the dopamien neurons to change L Dopa into dopamine and once they die the dopa doesn’t work
  • no disease modification! through this
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4
Q

What are the main issues with the current treatment of Parkinson’s?

A
  • Side-effects
  • Efficacy
  • No disease modification
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5
Q

What are the types of stem cells and how do they differ?

A

3 stem cell classes

  • totipotent= any cell in the embryo and placenta
  • pluripotent= from inner cell mass of blastocyst (can become anything in the embryo) (now can make these)
  • multipotent= more restricted, reflective of the tissue they come from, like neural stem cells can become neurons or glia
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6
Q

What are the main sources of neural stem cells?

A
  • we want neural stem cells here so they don’t grow into something else
  • either developing embryo or from an adult particularly in the hippocampus, and the lateral ventricle (SVZ) = for olfactory bulbs
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7
Q

What ways are being explored in how to make the dopaminergic neurons regenerate?

A
  • fetal and adult
  • this is looking at cell replacement therapy, or can do a chaperone cell or trophic cell (cell that will secrete trophic
  • induced pluripotent stem cells from patients= maybe to use
  • final option= activate quiscent population of stem cells in the brain SVZ and hippocampus (but really far away!)
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8
Q

What is special about the salamander’s ability to regenerate its neural cells?

A
  • salamander= extreme regenreation capabilities -can they grow midbrain dopaminergic neurons
  • kill the neurons and see what happens
  • cut coronal section and look
  • so test in salamander= inject amphetamine (causes release of dopamine from terminal and inhibits degradation)
  • at 3 days move only a bit, at 30 days move rapidly reflective of hyper dopamine state
  • amphetamine promotes DA release
  • correlate restoration of motor function with number of cells in the midbrain
  • in the lesion animals at 3 days only 10% motor function, as more cells in midbrain then get more motor function
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9
Q

What is most of the stem cell research going into?

A
  • research is mostly into stem cell replacement therapy
  • the issue here is that you are injecting into the forebrain instead of the midbrain to avoid the need to have the dopamine pathway
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10
Q

What was the human trial with injecting the dopamine neurons into the forebrain?

A
  • here transplanting new cell into the forebrain so don’t have to send long projections to the forebrain
  • lot of new cells in the brain and restore motor function to mice
  • human trials: -in some cases very successful, patient 3 years later complete motor function
  • 200% increase in dopamine levels in the hemisphere where the transplant was in, and 45% reduction in dopamine levels in the hemisphere the transplant was not in.
  • after 3 years!
  • the only success is using aborted fetal tissue
  • unfortunately it didn’t quite work
  • only 30% of people improved some had very bad side effects!
  • lot of variability in patients, only 30% robust improvement, 30% no effect, and 20% adverse debilitating effects
  • the issue with it was the variability with the donor tissue, storage, age of tissue etc. (make it more like the environment in which the neurons normally develop)
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11
Q

What are the ways in which we can improve the treatment of Parkinson’s where tissue is injected?

A

1. Standardization of donor tissue (& availability)

  • Isolation of appropriate DA neurons
  • Selective expansion of donor tissue
  • Standardization of pluripotent stem cells

2. Environments conducive to graft integration

  • Exposure to trophic cues
  • Promoting plasticity
  • Scaffolding support
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12
Q

How can you standardize the donor tissue?

A
  • want to control which type of DA neurons is coming in (motor-Substantia nigra not the reward-limbic)
  • can do this via brith dating analysis
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13
Q

How can you do the birth dating analysis to get the donor tissue standardized?

A
  • Current transplants of mouse embryonic day 12.5 (E12.5) VM with no knowledge DA neuron composition
  • Dopamine neurons are born from E10.5 to E14.5
  • Inject pregnant mouse at E10.5, E12.5 or E14.5 with BrdU (to label cells undergoing division)
  • Aim: Assess when dopamine neurons are born in the SNpc (motor) and VTZ (limbic/reward)
  • at E10.5 2-fold more GIRK/TH (motor) dopamine neurons
  • so target the E10.5 neurons!
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14
Q

What effect does the age of tissue have on the graft?

A
  • Younger donor tissue results in larger graft -as the motor DA neurons are on day E10.5 instead of the now used 12.5
  • younger tissue enriches for motor-like DA neurons
  • Younger donor tissue enhances striatal innervation, dorso-lateral fiber density & DA levels
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15
Q

Does younger tissue eliminate the issues with serotonin in the treatment?

A

-the side effects in the treatment= due to mishandling of dopamine by serotonin neurons, serotonin grows later so younger tissue doesn’t have it= get younger= better effects

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16
Q

What is a mitogen?

A
  • An agent that encourages a cell to commence cell division
  • epidermal growth factor
  • fibroblast growth factor
17
Q

What is a morphogen?

A
  • A protein (gradient) governing the position of various specialized cell types within a tissue.
  • Sonic hedgehog (Shh)
  • Fibroblast growth factors (FGF)
  • Wnts
18
Q

What is the second approach with developing stem cell treatment?

A
  • making the environment more like where the neurons develop normally
  • introducing the appropriate morphogens, mitogens and even semi-hypoxia
19
Q

What is the role of semi-hypoxia in stem cell treatment, what is the rationale behind using it?

A

second approach to mitigating the issues:

  • low O2 is more like the developing neurons
  • adopting knowledge from these studies and take younger tissue and use morphogens to enhance proliferation= tenfold increase in tissue so almost one to one (fetus to patient ratio, before it was 8:1)
20
Q

What effect does adding Wnt5 have on the graft?

A
  • increased growth
  • these proteins work and release dopamine
21
Q

What was the test with mice and transplanted tissue?

A
  • only one side of the brain has no dopamine
  • so have control and the animal will turn in circle and can use that as a measurement of parkinsons
  • can see how this behaviour decreases and from that determine how motor function is establishing
  • improved markedly with growth factors! Wnts and VMN
22
Q

Are there human trials about to begin with PD?

A
  • Selective expansion of human neural stem cells
  • Multi center trials about to commence
  • Still a limited tissue source
  • Ethical considerations
  • Potential for pluripotent stem cells
23
Q

What is the third approach to improving PD treatment?

A
  • looking at the use of pluripotent stem cells
    1. Regulating pluripotent stem cell differentiation
24
Q

Why would getting the pluripotent cell treatment be great and what are the challenges?

A

1. Unlimited cell source

  • Risk of neural overgrowth and tumors

2. Ability to generate all cell types

  • How to control DA differentiation

-Aims:

  • Identification of novel regulators in DA development
  • Refinement of DA differentiation from PSCs
25
Q

What are some of the advantages of using the pluripotent stem cells?

A
  • can get them anytime
  • store well
26
Q

What is the 4th thing to do in treatment?

A
  • Cell sorting of pluripotent-derived neurons
  • the ideal scenario
  • in reality get a mix of NS cells and mDA progenitors to the brain, and sometime the ES cells and this causes teratoma growth! to remove this option, have ways of removing the cells: next slide, the progenitors express green fluorescent protein so can tell them apart
27
Q

How can you sort out which pluripotent stem cell you have, which neurons it made?

A
  • attach reporter line
  • eg. GFP
  • then can sort them via fluorescence
28
Q

What is the 5th approach to the treatment?

A
  • Restoring DA connectivity following transplantation
  • the other approach: improving the host environment, improving the integration of teh graft
  • since most of the transplants are ectopic (forebrain) and don’t have the circuitry
  • Exploitation of DA axon guidance cues following transplantation (Identify dopamine axon growth and guidance cues in development)
  • here try to inject into the correct spot and guide them to the connection
  • Exploiting developmental trophins and guidance cues to promote graft integration (GDNF for example)
  • VM+GDNF =up to a seven fold increase in the axons, improvement in grafts!
29
Q

What is the 6th approach to the treatment?

A
  1. Alternative approaches for promoting graft plasticity
    - another way of improving the graft integration
    - if can promote plasticity of transplanted neurons
    - so have group with stimulating environment and group without
    - enrichment of the environment
    - the enriched group do much better!
30
Q

What is the 7th approach to the treatment?

A

7. Engineering scaffolds to support stem cell grafts in neural repair

  • another way of approaching it: improving the physical environment
  • provide surface for axons to grow on, use three types -aslo can functionalise the
  • nanofibrous scaffold, hydrogels and some mix it and make composite scaffolds
  • Modified scaffolds promote NSC proliferation & differntiation
  • Nanofibrous scaffold including GDNF immobilization promotes neural stem cell engraftment
31
Q

What is the prognosis to date?

A
  • Proof of principle for cell transplantation in PD
  • requires tissue standardization
  • requires alternative cell sources (availability/ethics)

Pluripotent stem cells (PSC) present viable options, especially iPSC for transplantation, drug discovery and disease modeling HOWEVER

  • PSCs require improved differentiation (>30% efficiency)
  • PSCs require guaranteed safety from persistent dividing cells and residual oncogenes (iPSCs)

This is rapidly progressing field but could still take many years to achieve the end point goal…

32
Q

What is the ideal for the future in terms of PD treatment?

A

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Neurophysiology (33 decks)

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