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Dopaminergic cell replacement therapy in Parkinson disease by Siddhartha Das
1. Progress in Dopaminergic Cell Replacement and
Regenerative Strategies for Parkinson’s Disease
SIDDHARTHA DAS PRAMANIK
M.PHARM 1ST YR
DEPARTMENT OF PHARMACEUTICAL ENGNEERING AND TECHNOLOGY, IIT BHU, VARANASI
2. INTRODUCTION
Parkinson’s disease (PD) is a chronic pro-gressive neurodegenerative disorder
symptomatically charac-terized by resting tremor, rigidity, bradykinesia, and
gait impairment. Most of the existing therapies for PD are based on the
replacement of dopamine, which is symptomatically effective in the early
stage but becomes increasingly less effective and is accompanied by serious
side effects in the advanced stages of the disease. Currently, there are no
strategies to slow neuronal degeneration or prevent the progression of
PD. Thus, the prospect of regenerating functional dopaminergic neurons is
very attractive.
5. • hfVM transplants earned positive results in both preclinical and
clinical tests.
• The clinical outcomes of hfVM transplantation were not always
consistent; some patients gained significant and stable improvements,
while others did not and even exhibited side effects.
• Due to tissue availability and ethical concerns, hfVM therapies will
never be the first choice
hfVM:
6. Stem cells
• Stem cells are a class of undifferentiated cells characterized by self-
renewal and potency to differentiate into specialized cell types,
• Stem cells are derived from two main sources: ESCs, and adult stem
cells, such as neural stem cells (NSCs) and mesenchymal stem cells
(MSCs)
• Alternatively, pluripotent stem cells can be generated from a source of
adult somatic cells by reprogramming (induced pluripotent stem cells,
iPSCs) or from chemically activated unfertilized oocytes (human
parthenogenetic stem cells, hpSCs).
7. NSCs
• generate progeny cells that terminally differentiate into neurons,
astrocytes, and oligodendrocytes in the central nervous system (CNS).
• NSCs are abundant in different regions of the fetal brain and persist in
restricted parts of the adult brain, notably the striatal (SVZ) and (SGZ)
of the hippocampus.
• However, NSCs from the embryonic or fetal brain still face similar
ethical problems as hfVM.
• ESCs or iPSCs, are more easily accessible, are readily available, and
exhibit plastic functions to generate targeted neural populations.
8.
9. ESCs
• Obtained from the inner cell mass of a blastocyst, ESCs are able to
differentiate into specialized cell types of three germ layers.
• human ESC differentiation protocols were refined to generate floor-
plate cells, first by inhibition of SMAD, high levels of Sonic hedgehog
(SHH), and activation of WNT1, followed by the generation of
midbrain DAn’s.
10. iPSCs
• Human iPSC technology holds great promise in the field of
regenerative medicine by generating patient-specific stem cells
without ethical concern.
• human somatic cells can be reprogrammed into human iPSCs
(hiPSCs) by using OSKM or an alternative TF combination.
• human iPSCs are currently generated using non-integrating vectors for
gene delivery, such as episomal DNAs and synthetic mRNAs.
13. DOPAMINERGIC NEURON
REGENERATIVE STRATEGIES
Direct Transdifferentiation-
• It is also termed direct lineage reprogramming, is a process that converts a specific somatic
cell type to another without tumorigenicity concerns by passing through a pluripotent state,
thus having advantages in clinical application over iPSCs and ESCs.
• DAn’s could be generated in the striatum by direct conversion of astrocytes using three
transcription factors, NeuroD1, Ascl1, and Lmx1a, and the microRNA miR-218
14. Endogenous Neuroregeneration-
• The discovery that neurogenesis still takes place in the SGZ and SVZ in the adult brain has
instigated intensive research into whether it is possible to rejuvenate the aging or diseased
brain by awakening endogenous regenerative capacity. Surprisingly, neurogenesis has also
been found to occur in other brain regions, such as the striatum and cortex, which are
considered to be nonneurogenic. However, whether DAn’s can be regenerated remains a
mystery.
• Administration of D3 dopamine receptor agonist 7-OH-DPAT could trigger a strong induction
of cell proliferation and dramatically increase TH+ neurons in the lesioned SN in a mouse 6-
OHDA model, suggesting that D3 receptor stimulation can evoke endogenous DAn
regeneration.
19. CONCLUSION
• As mentioned above, the different strategies to restore lost
function of the nigro-striatal circuit by replenishing DA
neurons have their pros and cons.
• Stable cell sources, such as ESCs and iPSCs, are far more
suitable for clinical application than hfVM- and embryonic or fetal
brain-derived NSCs.
• ESC-derived DA progenitors or NSCs have produced satisfactory
results in preclinical studies, but ethical concerns and risk of immune
rejection restrict their clinical practice.
20. REFERENCES
• Kalia, L. V., and Lang, A. E. (2015) Parkinson’s disease. Lancet386,
896−912.
• Olanow, C. W., Obeso, J. A., and Stocchi, F. (2006) Continuous
dopamine-receptor treatment of Parkinson’s disease: scientific
rationale and clinical implications. Lancet Neurol. 5, 677−687.
• Li, B., Gao, Y., Zhang, W., and Xu, J. R. (2018) Regulation and effects
of neurotrophic factors after neural stem cell transplantation in a
transgenic mouse model of Alzheimer disease. J. Neurosci. Res.
96,828−840.