Stem Cell Therapies for Alzheimer's Disease: Is It Time?

Sheng-Min Wang; Chang-Uk Lee; Hyun Kook Lima

Curr Opin Psychiatry. 2019;32(2):105-116.

Conclusion

Rapid development and advances indicate that it is timely to further stem cells therapy research in Alzheimer's disease. Various animal studies illustrated that stem cells may provide disease-modifying effect. In addition, recent research focused on the interplay of amyloid-beta Aβ (and tau), neurons, glia, direct regeneration of neurons and synapses, and antiinflammation as possible mechanism of action of stem cells in the treatment of Alzheimer's disease. Two completed and nine ongoing clinical trials using diverse stem cells and administration methods (intravenous and intra-cranial) were found for the treatment of Alzheimer's disease. However, the transgenic models used in animal studies were based on familial Alzheimer's disease hypotheses, which does not properly reflect general Alzheimer's disease in human. The two completed human trials both used stereotactic injections, so its safety and efficacy in other injection modalities including intravenous and intracranial must be confirmed. Thus, the stem cell therapy for Alzheimer's disease has now just passed infancy and entered toddlerhood. It is time to use these innovative techniques to illustrate not only potential, but also the prospects of stem cell therapy in the treatment of Alzheimer's disease.

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Acknowledgements
We would like to thank Dr Dong Woo Kang, Dr Hae-Ran Na, and Dr Min-Chung So for their contributions with the study. We also thank Hyeon-Ji Woo for helping with our figures.

Financial support and sponsorship
This research was supported by grant of the Institute of Clinical Medicine Research in the Yeouido St. Mary's hospital, Catholic University of Korea.

Table 1. Summary of stem cells commonly studied in treatment of Alzheimer's disease: animal mode
	Origin of stem cells			Type of cells
	Embryonic stem cell [23,24]	Umbilical cord blood/placenta stem cell [26-29]	Induced pluripotent stem cell [30,31]	Neural stem cell [37-40]	Mesenchymal stem cell [45,46]
Potency	Pluripotent	Multiplotent	Pluripotent	Multiplotent	Multiplotent
Differentiation	All germ layers	All CNS cells	All germ layers	All CNS cells	Neurons
Availability	Rare (blastocyst)	Abundant after normal delivery	Not in pure form, needs reprogramming	Small in brain	Abundant
Harvesting	Difficult, invasive Easy and not invasive	Easy and not invasive if after delivery	Difficult, needs reprogramming	Difficult, invasive Easy, not-	invasive Easy, not-invasive
Handling	Very difficult	Easy	Very difficult	Difficult	Easy
Mechanism	Migrate to Ach and GABA neuron	Reduce Aβ, BACE, tau. Reverse microglial neuro-inflammation. Promote anti-inflammatory cytokine, and others	Regeneration of depleted neural networks Neuronal differentiation	neurotrophic support of neurogenesis, synaptic connectivity, and others	Reduce Aβ, BACE, tau. Reverse microglial neuro-inflammation. Promote anti-inflammatory cytokine, and others
Tumor formation risk	Highest	Lower	Not confirmed, could be high	Lower	Lowest
Limitation	Immune rejection Ethical concern	Ethical concern for cord blood banks	Have least data immune rejection Displayed phenotypic neuropathology	Small number Difficult to harvest and handle	Limited lineages Limited survival short half-lives Infiltration to undesired organs

Aβ, amyloid beta; ACh, acetylcholine; BACE, beta-secretase; CNS, central nervous system; GABA, g-aminobutyric acid.

Table 2. Completed clinical trial trials of stem cells and G-cerebrospinal fluid in patients with Alzheimer's disease
Author	Kim etal. 2015 [59] (NCT0129721 8) [60]	Kim, 2015 [62] (NCT01696591)
Study date	2/2011-9/2011	3/2012-9/2013
Study length	12 weeks	2 years
Site	Korea	Korea
Subjects (age)	Probable AD+ MMSE 10–24 + Piβ-PET positive (50~75)	Subjects of NCT01297218
Design	Open label	Open label 24 months follow-up study of NCT01297218
Study phase	1	1
Stem cell used	HUC-MSC	HUC-MSC
Route (injection number)	Intra-cerebral (1)	No extra injection
Dosage (number of participants)	3 × 0 x l0⁶ cells/60 ml (3) 6.0 x 10⁶ cells/60 ml (6)	3 × 0 x l0⁶ cells/60 ml (3) 6.0 x 10⁶ cells/60 ml (6)
Total participants	9	9
Primary outcome measure	Number of AE	Number of AE
Secondary outcome measure	ADAS-Cog S-IADL MMSE, CGA-NPI Biomarkers: Piβ-PET FDG-PET, CSF Aβ and tau, serum transthyretin	ADAS-Cog, S-IADL MMSE, CGA-NPI, Biomarkers: Piβ-PET FDG-PET, CSF Aβ and tau, serum transthyretin
Results	Safety: no structural abnormalities (no tumor and SDH) Efficacy: MMSE change from baseline to week 12 (low dose: - 1 × 7 ± 0 × 6 high dose: - 0 × 5 ±2.1)	Safety: no structural abnormalities (no tumor and SDH) Efficacy: MMSE change from baseline to week 12 (low dose: -9.5 ±0.7 high dose: -8.4±5.6)

Aβ, amyloid-beta; AD, dementia because of Alzheimer's disease; ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive Subscale; AE, adverse events; CGA-NPI, Caregiver Administered Neuropsychiatric Inventory; CSF, cerebrospinal fluid; FDG-PET, fluorodeoxyglucose PET; HUC-MSC, human umbilical cord blood-derived mesenchymal stem cells; IADL, instrumental activities of daily living; MMSE, 3; NA, not available; Piβ-PET, Pittsburgh Compound B-PET; SDH, subdural hematoma; S-IADL, Seoul-instrumental activities of daily living.

Table 3. Ongoing clinical trial trials of stem cells in patients with Alzheimer's disease
Study name (study date)	Current state	Length (phase)	Site	Subjects (age)	Design	Stem cell	Route (n)	Dosage (participants)	N^a	Primary	Outcome measures Secondary
NCT01547689 [63] (3/2012 3–12/2016)	Not known	10 weeks (I/II)	China	Probable AD, NINCDS-ADRDA (50-85)	Open label, single group	HUC-MSC	IV (many)	0.5x10^6/kg (30)	30	AE number	ADAS-cog, CIBIC, CIBICplus, MMSE, ADL, NPI, biomarker (CSF Aβ, tau, etc.)
NCT03297177 [64] (1/2019-1/2023)	NR	0.5–5 years (I)	US	AD þ other neurological disease	Open label	A-SC	IV (NA)	NA	300	AE number	Neurological exam and MRI
NCT02833792 [65] (6/2016-6/2020)	Active, NR	18 months (IIa)	US	Mild-mod AD by NINCDS-ADRDA (55-80)	Single blind, crossover	H-MSC	IV (1)	1.5 x 10⁶/kg (20) PBO (20)	40	AE number	Neurological exam
NCT02600130 [69] (8/2016-10/2019)	Recruiting	52 weeks (I)	US	AD by NINCDS-ADRDA (50-80)	PBO-control Double-blind	H-MSC	IV (1)	20x 106 (10) l00x 10⁶ (10) PBO (5)	25	AE number	ADAS-cog, QOL-AD, NPI, MMSE, UPSIT, ADL, GDS, diverse biomarkers
NCT02672306 [68] (10/2017-10/2018)	Active, NR	48 weeks (I/II)	China	Mild-mod AD by NINDS-ADRDA (55-80)	PBO-control Double blind	HUC-MSC	IV (8)	0.5x10^6/kg (NA) PBO (NA)	40	ADAS-cog	AE, MMSE, CIBIC-plus, ADL, NPI, biomarker (plasma Aβ),
NCT03117738 [66] (3/2017-6/2019)	Recruiting	32 weeks (I/II)	US	Mild-mod AD by NINCDS-ADRDA (> 50)	PBO-control, Double-blind	AD-MSC	IV (9)	1xl0^7/kg (30) PBO (30)	60	ADAS-cog	MMSE, CDR-SB, NPI, GDS, ADL, biomarker (MRI, Aβ, etc.)
NCT02 899091 [67] (9/2016-6/2018)	Not known	48 weeks (I/IIa)	Korea	Probable AD by NINCDS-ADRDA (>50) with (Ab PET)	PBO-control, Double-blind, Two stage	PD-MSC	IC(4)	2.0x 10^8 (12) PBO (12)	24	AE number	ADAS-cog, GDS, CDR, NPI, MMSE, K-IADL, CIBIC-plus, SF-36, biomarker (Aβ-PET and FDG-PET, MRI, CSF, etc.)
NCT02054208 [70] (2/2014-7/2019)	Recruiting	24 weeks (I/IIa)	Korea	Mild-mod AD by NINCDS-ADRDA (50-85)	PBO-control Double blind Two stage	HUC-MSC	IV (3)	1 x 10 ^ 7/2 ml (3) 3x10^7/2 ml (30) PBO (12)	45	AE number	ADAS-cog, S-IADL, MMSE, CGA-NPI, CDR-SB, CIBIC-plus, biomarker (PiB and FDG PET, MRI, CSF)
NCT03172117 [7] (5/2017-12/2021)	Recruiting	36 months (I/IIa)	Korea	Subjects of NCT02054208	Follow-up study	HUC-MSC	No extra	Identical to NCT02054208	45	ADAS-cog	Identical to NCT02054208 except for ADAS-Cog

Aß, amyloid-beta; AD, dementia because of Alzheimer's disease ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADL, Alzheimer's disease cooperative study activities of daily living AD-MSC, adipose tissue-derived mesenchymal stem cells; AE, adverse events; A-SC, autologous stem cell; CDR, Clinical Dementia Rating Scale; CDR-SB, Clinical Dementia Rating-Sum Administered Neuropsychiatric Inventory; CIBIC, Change in Clinician's Dementia Rating-Sum of Boxes; CGA-NPI, Caregiver Administered Neuropsychiatric Inventory; CIBIC, Change in Clinician's Interview-based Impression of Cha Clinician's Interview-based Impression of Change; CSF, cerebrospinal fluid; FDG, fl uorodeoxyglucose; GDS, Global Deterioration Scale; H-MSC, human mesenchymal stem cells; HUC-MSC, human umbilical cord blood-derived mesenchymal stem cells; IC, intraventricular; IV, intravenous; MMSE, Mini-Mental State Examination; NA, not National available; NINCDS-ADRDA, National nstitute of Neurological and Communicative Disorders and Stroke and the Alzheimer' s Disease and Related Disorders Association; NR, not recruiting; PBO, placebo; PD-MSC, placenta-derived mesenchymal stem cell; PiB, Pittsburgh Compound B; QOL-AD, Quality o life-Alzheimer's disease; SF-36, The Short Form (36) Health Survey; S-IADL, Seoul-instrumental activities of daily living; UPSIT, University of Pennsylvania Smell Identification Test.
^aNumber of total participants.

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