A systematic review of clinical efficacy and safety of cell-based therapies in Alzheimer’s disease

Feizi, Hamidreza; Hosseini, Mohammad-Salar; Seyedi-Sahebari, Sepideh; Karimi, Hanie; Mosaddeghi-Heris, Reza; Sadigh-Eteghad, Saeed; Sadeghi-Ghyassi, Fatemeh; Talebi, Mahnaz; Naseri, Amirreza; Salehi-Pourmehr, Hanieh; Roshangar, Leila

doi:10.1590/1980-5764-DN-2024-0147

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Dementia & Neuropsychologia

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View and Review • Dement. neuropsychol. 18 • 2024 • https://doi.org/10.1590/1980-5764-DN-2024-0147 copy

A systematic review of clinical efficacy and safety of cell-based therapies in Alzheimer’s disease

Uma revisão sistemática da eficácia clínica e segurança das terapias baseadas em células na doença de Alzheimer

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

There is presently no disease-modifying therapy for Alzheimer’s Disease (AD), which is the most prevalent cause of dementia.

Objective:

This study aspires to estimate the efficacy and safety of cell-based treatments in AD.

Methods:

Observing the Joanna Briggs Institute (JBI) methods and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic search was accomplished in PubMed, Medical Literature Analysis and Retrieval System Online (Medline, via Ovid), Embase; Cochrane, and Cumulative Index of Nursing and Allied Health Literature — CINAHL (via EBSCO) databases up to June 2023. The relevant clinical studies in which cell-based therapies were utilized to manage AD were included. The risk of bias was evaluated using the JBI checklists, based on the study designs.

Results:

Out of 1,014 screened records, a total of five studies with 70 individuals (including 59 patients receiving stem cells and 11 placebo controls) were included. In all these studies, despite the discrepancy in the origin of stem cells, cell density, and transplant site, safety goals were obtained. The intracerebroventricular injection of adipose-derived stromal vascular fraction (ADSVF) and umbilical cord-derived mesenchymal stem cells (UC-MSCs), the intravenous injection of Lomecel-B, and the bilateral hippocampi and right precuneus injection of UC-MSCs are not linked to any significant safety concerns, according to the five included studies. Studies also revealed improvements in biomarkers and clinical outcomes as a secondary outcome. Three studies had no control groups and there are concerns regarding the similarity of the groups in others. Also, there is considerable risk of bias regarding the outcome assessment scales.

Conclusion:

Cell-based therapies are well tolerated by AD patients, which emphasizes the need for further, carefully planned randomized studies to reach evidence-based clinical recommendations in this respect.

Keywords:
Alzheimer Disease; Cell Transplantation; Stem Cell Transplantation; Systematic Review

	P: patients				I: Intervention				O: outcome
Study	Baseline MMSE	N	M:F	Mean age ± SD	Types of SCT	Cell density	Where cells derived	Transplantation zone	Intervention-outcome measurement interval	Outcome assessment scales	Summary of results	Cognitive outcomes
Kim et al.²⁴24. Kim HJ, Seo SW, Chang JW, Lee JI, Kim CH, Chin J, et al. Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase 1 clinical trial. Alzheimers Dement (N Y). 2015;1(2):95-102. https://doi.org/10.1016/j.trci.2015.06.007 https://doi.org/10.1016/j.trci.2015.06.0...	16.6±4.1	9	6:3	61.6±6.9	human UC-MSCs	(3, 6)×10⁶6. Rasi Marzabadi L, Fazljou SMB, Araj-Khodaei M, Sadigh-Eteghad S, Naseri A, Talebi M. Saffron reduces some inflammation and oxidative stress markers in donepezil-treated mild-to-moderate Alzheimer’s Disease patients: a randomized double-blind placebo-control trial. J Herb Med. 2022;34:100574. https://doi.org/10.1016/j.hermed.2022.100574 https://doi.org/10.1016/j.hermed.2022.10... cells	umbilical cord blood	bilateral hippocampi and right precuneus	4, 12 weeks, and 24 months	ADAS-Cog, S-IADL, MMSE, PiB-PET, FDG-PET, CSF biomarkers, brain CT and MRI	In the 12-week follow-up, wound pain (100%), headache (44.4%), dizziness (33.3%), delirium (33.3%), nausea (22.2%), and back pain (22.2%) were the most common adverse events, none of which were extended to 24 months. There were no structural abnormalities or immunological reactions.	Changes in ADAS-Cog, in the low-dose group, were 5.3±3.5 (week 12) and 20.0±9.9 (month 24); in the high-dose group, they were 3.5±5.6 (week 12) and 8.6±13.1 (month 24). Changes in S-IADL, in the low-dose group, were 1.7±4.0 (week 12) and 19.5±6.4 (month 24); in the high-dose group, they were 1.2±5.9 (week 12) and 12.0±6.0 (month 24). Changes in MMSE, in the low-dose group, were -1.7±0.6 (week 12) and -9.5±0.7 (month 24); in the high-dose group, they were 0.5±2.1 (week 12) and -8.4±5.6 (month 24).
Duma et al.²³23. Duma C, Kopyov O, Kopyov A, Berman M, Lander E, Berman S, et al. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction for neurodegenerative disorders: a 3-year phase 1 study of 113 injections in 31 patients. Stereotact Funct Neurosurg. 2019;97(suppl 1):111.	Various	10	6:4	75.5±11.6	ADSVF	3.5–20 cc containing 4.05×10⁵5. Majidazar R, Rezazadeh-Gavgani E, Sadigh-Eteghad S, Naseri A. Pharmacotherapy of Alzheimer’s disease: an overview of systematic reviews. Eur J Clin Pharmacol. 2022;78(10):1567-87. https://doi.org/10.1007/s00228-022-03363-6 https://doi.org/10.1007/s00228-022-03363... to 6.2×10⁷7. Vo TS, Vo TTBC, Vo TTTN. Characterization and heath effects of saffron utilizing in disease treatment and prevention: a review. J Res Clin Med. 2021;9(1):28. https://doi.org/10.34172/jrcm.2021.028 https://doi.org/10.34172/jrcm.2021.028... cells/cc	liposuction	Intracerebroventricular (Ommaya reservoir implantation)	2 to 36 months	MPI, RBANS, NeuroQuant^® volumetric MRI, CSF biomarkers	There was no complication other than mild headache, or pain at the surgical sites, for less than 24 hours. Over eight months, 30% showed an improvement in CSF markers. Hippocampal volume increased in one of four assessed AD patients after 2 years of follow-up.	Over eight months, 80% of AD patients had stable or improved cognitive function, assessed by MPI.
Kim et al.²²22. Kim HJ, Cho KR, Jang H, Lee NK, Jung YH, Kim JP, et al. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial. Alzheimers Res Ther. 2021;13(1):154. https://doi.org/10.1186/s13195-021-00897-2 https://doi.org/10.1186/s13195-021-00897...	21.1±3.82	9	3:6	62.7±7.93	human UC-MSCs	(1-3)×10⁷7. Vo TS, Vo TTBC, Vo TTTN. Characterization and heath effects of saffron utilizing in disease treatment and prevention: a review. J Res Clin Med. 2021;9(1):28. https://doi.org/10.34172/jrcm.2021.028 https://doi.org/10.34172/jrcm.2021.028... cells/2 mL [three repeated injections]	umbilical cord blood	Intracerebroventricular (Ommaya reservoir implantation)	4,8, 12, 52, 104 weeks	ADAS-Cog, S-IADL, MMSE, NPI, CIBIC-Plus, CSF biomarkers, MRI, PiB-PET or florbetaben PET	Fever (100%), headache (77.8%), nausea (55.6%), vomiting (44.4%), myalgia or chills (22.2%), paresthesia on both arms and legs (22.2%) were the most commonly reported adverse events, all of which subsided within 36 hours. There were also three serious adverse events in two participants which required an extended hospitalization.	Changes in ADAS-Cog, in the low-dose group were 0.7±4.0, and in the high-dose group, were 2.3±5.0 (week 12) Changes in S-IADL, in the low-dose group were 2.0±2.0, and in the high-dose group were 1.5±3.0 (week 12) Changes in MMSE, in the low-dose group, were 0.0±2.0, and, in the high-dose group were 0.7±1.6 (week 12). Changes in NPI, in the low-dose group, were 1.3±2.3, and, in the high-dose group, were -1.7±5.8 (week 12).
Myeong et al. ²¹21. Myeong SH, Kim H, Lee NK, Hwang JW, Kim HJ, Jang H, et al. Intracerebroventricular administration of human umbilical cord blood-derived mesenchymal stem cells induces transient inflammation in a transgenic mouse model and patients with Alzheimer’s disease. Biomedicines. 2022;10(3):563. https://doi.org/10.3390/biomedicines10030563 https://doi.org/10.3390/biomedicines1003...	21.6±1.39	6 (+3 placebo)	5:4	63.4±3.64	human UC-MSCs	3×10⁷7. Vo TS, Vo TTBC, Vo TTTN. Characterization and heath effects of saffron utilizing in disease treatment and prevention: a review. J Res Clin Med. 2021;9(1):28. https://doi.org/10.34172/jrcm.2021.028 https://doi.org/10.34172/jrcm.2021.028... cells/2 mL	umbilical cord blood	Intracerebroventricular (Ommaya reservoir implantation)	24 hours	CSF pro-inflammatory cytokine	Injection was associated with increased CSF levels of TNF-α, IL-1β, IL-6, and CRP; however, bacterial culture results were negative.	-
Brody et al.²⁵25. Brody M, Agronin M, Herskowitz BJ, Bookheimer SY, Small GW, Hitchinson B, et al. Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer’s disease. Alzheimers Dement. 2023;19(1):261-73. https://doi.org/10.1002/alz.12651 https://doi.org/10.1002/alz.12651...	20.45±1.46, 20.60±2.06, 20.70±2.26	25 (+ 8 placebo)	17:16	71.2±8.4	Lomecel-B	(2-10)×10⁷7. Vo TS, Vo TTBC, Vo TTTN. Characterization and heath effects of saffron utilizing in disease treatment and prevention: a review. J Res Clin Med. 2021;9(1):28. https://doi.org/10.34172/jrcm.2021.028 https://doi.org/10.34172/jrcm.2021.028... cells	Bone marrow	single intravenous infusion	13, 26, 52 weeks	MMSE, ADAS-Cog-11, ADCS-ADL, ADRQL, GDS, NPI, QOL-AD, Trail Making Test, plasma biomarkers, MRI	There was only one treatment-emergent serious adverse event. The incidence of adverse events was lower in each Lomecel-B treatment arm. There were no amyloid-related imaging abnormalities.	Low-dose (but not high-dose) Lomecel-B arm was significantly better than the placebo at week 13 by 2.69±1.39 points in MMSE. Lomecel-B arms appeared more stable in ADAS-Cog-11, and the difference at week 26 between placebo and low-dose Lomecel-B arms, while not significant, was 5.68±3.66.

Questions	Author (year)
Questions	Myeong et al.²¹21. Myeong SH, Kim H, Lee NK, Hwang JW, Kim HJ, Jang H, et al. Intracerebroventricular administration of human umbilical cord blood-derived mesenchymal stem cells induces transient inflammation in a transgenic mouse model and patients with Alzheimer’s disease. Biomedicines. 2022;10(3):563. https://doi.org/10.3390/biomedicines10030563 https://doi.org/10.3390/biomedicines1003...	Brody et al.²⁵25. Brody M, Agronin M, Herskowitz BJ, Bookheimer SY, Small GW, Hitchinson B, et al. Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer’s disease. Alzheimers Dement. 2023;19(1):261-73. https://doi.org/10.1002/alz.12651 https://doi.org/10.1002/alz.12651...	Kim et al.²²22. Kim HJ, Cho KR, Jang H, Lee NK, Jung YH, Kim JP, et al. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial. Alzheimers Res Ther. 2021;13(1):154. https://doi.org/10.1186/s13195-021-00897-2 https://doi.org/10.1186/s13195-021-00897...	Duna et al.²³23. Duma C, Kopyov O, Kopyov A, Berman M, Lander E, Berman S, et al. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction for neurodegenerative disorders: a 3-year phase 1 study of 113 injections in 31 patients. Stereotact Funct Neurosurg. 2019;97(suppl 1):111.	Kim et al.²⁴24. Kim HJ, Seo SW, Chang JW, Lee JI, Kim CH, Chin J, et al. Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase 1 clinical trial. Alzheimers Dement (N Y). 2015;1(2):95-102. https://doi.org/10.1016/j.trci.2015.06.007 https://doi.org/10.1016/j.trci.2015.06.0...
Q1: Is it clear in the study what the ‘cause’ is and what the ‘effect’ is (i.e. is there no confusion about which variable comes first)?	Y	Y	Y	Y	Y
Q2: Were the participants included in any similar comparisons?	U	U	N	U	N
Q3: Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?	U	U	N	N	N
Q4: Was there a control group?	Y	Y	N	N	N
Q5: Was the data analysis conducted with sufficient coverage of the identified sample?	Y	Y	Y	U	Y
Q6: Was follow-up complete? And, if not, were differences between groups in terms of their follow-up adequately described and analyzed?	N	Y	Y	N	Y
Q7: Were the outcomes of participants included in any comparisons measured in the same way?	Y	Y	Y	Y	Y
Q8: Were outcomes measured in a reliable way?	U	Y	U	U	U
Q9: Was appropriate statistical analysis used?	Y	U	N	U	N

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E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[1] Correspondence: Hanieh Salehi-Pourmehr; Email: salehiha@tbzmed.ac.ir.