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Printable Handouts
Navigable Slide Index
- Intro slide
- The classical pathology of Parkinson's disease
- Treatment strategies in PD
- Criteria for any cell therapy to be used in PD
- Experimental data on neural grafts: summary
- Clinical effects of fetal nigral allografts
- Freed et al trial of neural grafting in PD
- Olanow et al trial of neural grafting in PD: design
- Olanow et al trial of neural grafting: results
- Summary of clinical data on neural allografts in PD
- The issues facing neural grafting in PD
- The real pathology of PD
- Clinical spectrum of signs and symptoms in PD
- Thus the remit for any cell therapy in PD
- Different cells that could be used in PD
- Xenografts
- Obstacle 1: zoonotic infection
- Paradis et al study on PERVs
- Van der Laan et al study on PERVs
- Obstacle 2: risk of rejection
- The CD8 cellular rejection response
- Obstacle 3: functional capacity of xenografts
- Stem cells
- Why consider stem cells for grafting?
- Types of stem cells
- How might stem cells be used in treating PD
- Transplantation of exogenously derived stem cells
- Embryonic neural stem cells (NSCs)
- What must embryonic NSCs be able to do?
- Embryonic NSCs in vitro: growth potential
- Embyonic neural stem cell differentiation in vitro
- Problems with embryonic NSCs: general
- Changes in embryonic NSC behaviour over time
- The problems with their terminal differentiation
- ES cells and dopmainergic differentitiation
- Conclusion on stem cells forming dopamine cells
- Can such cells repair brains?
- Porcine NSC transplant study
- Transplant survival
- Transplant differentiation
- Presence of Dopaminergic cells
- Circuit reconstruction (1)
- Circuit reconstruction (2)
- Functional outcome
- Conclusion on stem cell transplants in PD to date
- Cells for grafting: conclusion
- Where should transplants be placed?
- Summary of data to date
- Nigrostrital circuit reconstruction data to date
- Topography of nigrostriatal dopaminergic projection
- Conclusion on where grafts should be placed
- When should patients be grafted
- The stages of PD and origin of dyskinesais
- The treatment of PD by stage
- Conclusion on when should patients be grafted
- Which patients should be grafted?
- The heterogeneity of PD
- The CamPaIGN study design
- Defining PD heterogeneity
- Motor phenotypes
- Motor phenotypes in the CamPaIGN study
- Cognitive phenotypes
- Cognitive phenotypes in the CamPaIGN study
- Verbal working memory in PD
- fMRI changes with manipulation on VWMT
- But what causes these differences?
- COMT and BDNF
- Comt and BDNF polymorphisms
- A tentative classification of PD
- Conclusion on which patients should be grafted
- Overall conclusion
- Acknowledgements
- Speaker details
Topics Covered
- Pathological features of Parkinson's disease
- Limitations of current drug therapies
- Possible alternative therapies
- Deep brain stimulation
- Growth factor infusions
- Neural transplants
- Human fetal allograph transplants
- Issues facing neural grafting in PD
- Implications for cell therapies for all neurological disorders
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Barker, R. (2020, December 2). Parkinson's disease and transplants [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 9, 2024, from https://doi.org/10.69645/NQLW6197.Export Citation (RIS)
Publication History
Financial Disclosures
- There are no commercial/financial matters to disclose.
Update Available
The speaker addresses developments since the publication of the original talk. We recommend listening to the associated update as well as the lecture.
- Full lecture Duration: 61:09 min
- Update Interview Duration: 8:20 min
A selection of talks on Neurology
Transcript
Please wait while the transcript is being prepared...
0:00
In this talk, I'm going to discuss Parkinson's disease,
possible repair of the brain in this condition, during neural transplant.
In particular, I'm going to discuss which types of
cells are best considered as a reparative therapy,
where they should be transplanted in the Parkinsonian brain, and in whom.
However, before discussing these issues,
it is important to remind ourselves about Parkinson's disease.
0:23
Parkinson's disease is classically thought of as a disorder of the basal ganglia,
which is fundamentally characterized by the loss of dopamine in
the nigrostriatal pathway and the formation of
Alpha-synuclein Lewy bodies within the substantia nigra.
This loss of dopaminergic tone within the network leads to
the classical motor triad of arresting pill roll tremor,
bradykinesia or slowness of movement, and rigidity.
0:48
Knowing that this was the core pathological event in Parkinson's disease,
leads to the obvious therapeutic manipulation of replacing it through drug therapies.
In the late 1950s,
it was discovered that this was the major pathological deficit in Parkinson's disease,
which led to the use of levodopa in the 1960s.
This therapy continues to be the mainstay of treatment,
and is converted and works by being converted into dopamine in the Parkinsonian brain.
Alternative strategies using drugs have also being pursued,
including the use of selective dopamine receptor agonist,
as well as anticholinergic drugs.
Indeed, in the more advanced stages of disease,
there are a number of other manipulations that can be
done to enhance the efficacy of these drugs,
including the use of various COMT and monoamine oxidase inhibitors,
as well as amantadine, which can deal with the drug-induced dyskinesias.
Indeed, drug-induced dyskinesias are one of the major complications of drug therapy,
with about 10 percent of patients per treatment year developing this phenomenon.
This involves involuntary dyskinetic movements,
typically at the peak dose of levodopa when the patients have taken their drugs.
As a result of this, alternative strategies are being pursued to
help patients as they move towards the more advanced stages of disease.
This is including the continuous stimulation of
dopamine receptors using apomorphine infusions,
as well as various neurosurgical interventions.
Initially, this took the form of lesioning either of
the internal part of the globus pallidus or the subthalamic nucleus.
But of late has been superseded by the use of
deep brain stimulation bilaterally to the subthalamic nucleus.
Whilst all of these therapies are effective symptomatically,
none of them are curative,
as a result of which, other approaches have been taken,
which are designed to actually repair the Parkinsonian brain.
Of late great interest has been shown in the use of GDNF infusions.
This factor, glial cell line-derived neurotrophic factor,
is a growth factor for dopaminergic cells.
In a pilot study done by Steven Gill and colleagues down in Bristol,
it was shown that the direct intraputaminal,
so directly into the basal ganglion, infusion
this growth factor produced a clinical improvement in five patients,
which correlated with an increase in dopamine on fluorodopa PET scanning.
Indeed, one of these patients who subsequently died from unrelated causes,
was found at post-mortem to have sprouting of
dopaminergic fibers around the site of GDNF infusion.
Whilst this therapy looks extremely effective,
a recent double-blind placebo-controlled trial sponsored by the company that make GDNF,
namely Amgen, has produced less significant results.
There have also been a number of reports of
side effects and pathological complications in experimental animals,
which is lead currently to this factor not being used widely in Parkinson's disease.
As a result of which other approaches have been used adopting a similar strategy,
but in this case, linking the growth factor to viral vectors.
It is yet to be seen whether this approach prove to be successful without side effects.
The final approach to treating
the Parkinsonian brain is that which involves replacing the cells through
cell transplantation and it is this that will form the mainstay of my talk.
In particular, I'm going to start by discussing what has been
achieved with this approach to date experimentally and then clinically.
If we are to use cell therapists to repair the Parkinsonian brain,