Stem cell therapy shows promise for treating various neurological disorders. There are two main types of stem cells - embryonic stem cells which are pluripotent, and adult stem cells which are multipotent. Stem cells may promote cell replacement in damaged organs through proliferation, migration, and differentiation. Challenges include optimal cell types and doses, monitoring transplanted cells, and ensuring safety. While stem cell therapy is being studied for conditions like Alzheimer's, Parkinson's, ALS, and stroke, more research is still needed to address current obstacles in translating laboratory findings to clinical applications.

1. Stem cell therapy in neurological disorders
DR SWAPNIL SAMADHIYA
SR NEUROLOGY
GMC KOTA

3. Goal of stem cell therapy
• To promote cell replacement in organs that are damaged beyond
their ability to self-repair.

4. Stem cell therapy and classification

5. Embryonic S.C. Adult S.C.
From blastocysts , In-Vitro
Fertilization and aborted fetuses
Stem cells have been found in the
blood, bone marrow, liver, kidney,
brain, etc
“Pluripotent”
(can become any cell)
“Multipotent”
(can become many but not any)
Stable. Can undergo many cell
divisions.
Less Stable. Capacity for self-
renewal is limited.
Easy to obtain but blastocyst is
destroyed.
Difficult to isolate in adult tissue.
Possibility of rejection?? Host rejection is minimal
Ethical issues No ethical issues 5

6. What’s special about and potential???
(A) Proliferate in vitro (large numbers of cells can be derived).
(B) Patient own cells have harvesting potential.
(C) Following implantation ability to migrate and disseminate.
(D) Tropism for areas of pathology.
(E) Ease of manipulation(viral and non-viral gene transfer).
(F) Integrate into normal brain cytoarchitecture & physiologically
regulated release of substances.

7. Sites of adult neuronal stem cells
• Subventricular zone(SVZ) of lateral ventricles
• Subgranular zone of dentate gyrus in hippocampus
Kornblum HI. Introduction to neural stem cells. Stroke. 2007 Feb;38(2 Suppl):810-6. doi: 10.1161/01.STR.0000255757.12198.0f. PMID:
17261745.

8. Nuclear Reprogramming
• N. Development -totipotent (zygote) –
pluripotent cells(blastocyst) -
multipotent fertilized cells -terminally
differentiated cells.
• The reversal of the terminally
differentiated cells to totipotent or
pluripotent cells (called nuclear
reprogramming).
• Using nuclear transplantation or
nuclear transfer (NT), procedures
(“cloning”),nucleus of a differentiated
cell is transferred into an enucleated
oocyte.
• Error-prone procedure with a very low
success rate.

9. Transdifferentiation (stem cells plasticity)
iPS-
• An alternative approach,method of choice is induced pluripotent stem [iPS]using various transcription
factors(TFs).
Direct reprogramming-
• One type of terminally differentiated cell ( Fibroblast cell) into another type of terminally differentiated cell
(Neuron) by overexpressing specific sets of TFs .
• Currently limited by its low efficiency.

10. Hayflick limit

11. Mechanism of action

12. Essential properties of stem cells for use in clinical
transplantation
• Capable of clonal propagation in vitro(ensure homogeneity)
• Genetic stability at high passage
• Integration within the host brain following transplantation
• Connectivity within host circuits
• Migration and engraftment at sites of damage
• Correct differentiation into appropriate neural cell types
• Functional benefits
• Lack of side effects

13. Routes of stem cell therapy

14. Therapeutic uses

15. Alzheimers disease
• Neurogenesis in
the hippocampus
decreases with
age and is
exacerbated in
AD
• Cellular therapies
which enhance
neurogenesis or
replace lost
neurons may
delay the
progression of
AD.

16. Parkinson’s disease

17. • SB623 is a cell therapy derived from bone marrow
mesenchymal stem cells (MSCs) that has
immunosuppressive and angiogenic effects.
• Intracranial injection of SB623 gene.
• Positive results in animal models.
Tate CC, Chou VP, Campos C, Moalem AS, Di Monte DA, McGrogan M, Case CC, Manning-Bog AB. Mesenchymal stromal SB623 cell
implantation mitigates nigrostriatal dopaminergic damage in a mouse model of Parkinson's disease. J Tissue Eng Regen Med.
2017 Jun;11(6):1835-1843. doi: 10.1002/term.2081. Epub 2015 Oct 6. PMID: 26440859.

19. Huntington’s disease
• At this time,delivery of trophic factors and neuroprotection
to prevent disease progression seems more achievable than
neuronal replacement.

21. Amyotrophic lateral sclerosis
• Many studies have indicated that it is possible to generate
motor neurons in culture from stem cells that include ESCs
and NSCs.
• Human ESCs transplanted into cerebrospinal fluid of rats with
motor neuron injury migrated into the spinal cord and led to
improved motor function.
• Replacement of damaged motor neurons in ALS is not
currently practical in humans, the focus instead is on
neuroprotection.

23. MULTIPLE SCLEROSIS

24. Stroke
• 70% of the studies, MSCs were used.
• Multiple cell types affected by stroke, robust and long-lasting
regeneration for stroke appears very difficult
• Therapeutic effects mediated by angiogenesis, anti-inflammation,
antiapoptosis, neurogenesis with subsequent cell migration, and
differentiation.
Li G, Yu F, Lei T, et al. Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment
optimization strategies. Neural Regen Res. 2016;11:1015-1024

27. Spinal muscular atrophy
• Current pharmaceutical developments and gene therapy treatments
focus on regulating SMN2 to treat SMA.
• Cellular therapies, however, have been examined in mouse models of
SMA, where grafting of ES derived NPCs protected MNs from
degeneration and improved survival
• The correction of SMNgene, using single stranded oligonucleotide,
was shown to restore the SMN gene profile in neurons derived from
SMA-iPSC, converting SMN2 in SMN1
Corti S, Nizzardo M, Nardini M, et al. Neural stem cell transplantation can ameliorate the phenotype of a mouse
model of spinal muscular atrophy. J Clin Invest. 2008;118(10):3316–3330

28. Traumatic Brain/Spinal Cord injury
• Transplanting neural stem cell (injury sites).
• Side effect seen due to the addition of inappropriate circuitry.
• Preventing scar tissue(help growth of neural projection).
• Considered a chronic disease because of the secondary inflammatory
response that accompanies the initial insult
Azouvi P, Vallat-Azouvi C, Belmont A. Cognitive deficits after traumatic coma. Prog Brain Res. 20 09;177:89-110

30. Cerebral Palsy

33. Autism

34. Sharma A, Gokulchandran N, Sane H, Nagrajan A, Paranjape A, et al. Autologous bone marrow mononuclear cell
therapy for autism – An open label proof of concept study. Stem Cells International. 2013;2013:13 pages. Article
ID 623875

35. DMD

36. Sharma A, Sane H, Badhe P, Gokulchandran N, Kulkarni P, Lohiya M,
Biju H, Jacob VC.
A clinical study shows safety and efficacy of autologous bone marrow
mononuclear cell
therapy to improve quality of life in muscular dystrophy patients.
Cell Transplantation.
2013;22(Suppl 1):S127‐S138

37. APPLICATIONS OF NSCs AS VECTORS FOR THE DELIVERY OF
BIOLOGICALLY ACTIVE SUBSTANCES
Treatment of genetic disorders
• Inherited neurological conditions ,loss of function of a single gene,encoding
metabolically or developmentally critical enzyme
• Deliver functional enzymes diffusely
• Animal models such as that for mucopolysaccharidosis type VII (MPS VII,
Morquio)
Snyder EY, Taylor RM, Wolfe JH. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse
brain. Nature1995;374:367–70

38. Neurotrophins and cytokines
for neuroprotection
1. Attractive compared to viral
vector based delivery
system.
2. Host brain not genetically
manipulated.
3. Prevent insertional
mutagenesis.
4. Preserving the function of
neurons in the host.
5. Level of production of the
growth factor can be
standardised.
6. Extra safety features
“suicide cassette”.
Arenas E. Stem cells in the treatment of
Parkinson’s disease. Brain Res
Bull2002;57:795–80

39. Chemotherapeutic agents

42. CURRENT OBSTACLES
LABORATORY‐TO‐CLINIC PROGRESS
• Difficulty in synapse formation(electrical stimulation)
• Risks for tumorigenesis(fetal cells)
• Transplantation‐related mortality (umbilical cord stem cells,slow or
incomplete immune reconstitution)
• Time to convert these cells into the desired cell phenotype(>3 wk)
• Cost ($15000)
• Inter-clonal differences
• Nonhomogeneity of differentiation
• Ethical consideration

43. Unresolved issues with the cell therapy
• The optimal type of cells
• Dosage of cell
• Optimum timing of treatment
• Optimum route of delivery
• Outcome measures- primary safety end points and efficacy
measurements.

44. Future directions-
• In-vivo tracking of transplanted cells.
• Labelling of cells with a magnetic label (eg Super paramagnetic iron
oxide particles)-MRI tracking
• Long-term biosafety studies are essential because of potential for
tumorogenicity.
• Appropriate quality assurance and control standards must be in place
to allow the standardization of cell preparations

45. Carry home message

46. References
1. Varma SK, Hyder MK, Som S, et al. Stem cell therapy: in treatment of
neurodegenerative diseases. J Stem Cell Res Ther.2018;4(1):4‒7 .
DOI: 10.15406/jsrt.2018.04.00105
2. STEM CELL THERAPY FOR NEUROLOGICAL DISORDERS: A FOCUS ON
AGING Hung Nguyen, Sydney Zarriello, Alexandreya Coats, Cannon
Nelson, Chase Kingsbury, Anna Gorsky, Mira Rajani, Elliot G. Neal,
and Cesar V. Borlongan doi:10.1016/j.nbd.2018.09.011
3. Stem Cell Therapy in Pediatric Neurological Disabilities Alok Sharma,
Hemangi Sane,Nandini Gokulchandran, Prerna Badhe,Pooja Kulkarni,
Suhasini Pai, Ritu Varghese and Amruta Paranjape
http://dx.doi.org/10.5772/67656
4. Stem Cell Therapy for Neurodegenerative Diseases Jong Zin Yee,Ki-
Wook Oh,Seung Hyun Kim
http://dx.doi.org/10.7599/hmr.2015.35.4.229
5. Harissons principle of internal medicine 20 th edition

47. Thank you