Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer's disease: a phase I/II clinical trial

Abstract

Background: There have been no effective treatments for slowing or reversing Alzheimer's disease (AD) until now. Growing preclinical evidence, including this study, suggests that mesenchymal stem cells-secreted exosomes (MSCs-Exos) have the potential to cure AD.

Aims: The first three-arm, drug-intervention, phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos (ahaMSCs-Exos) in patients with mild to moderate AD.

Methods: The eligible subjects were assigned to one of three dosage groups, intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks, and underwent follow-up visits at weeks 16, 24, 36 and 48.

Results: No adverse events were reported. In the medium-dose arm, Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-cog) scores decreased by 2.33 (1.19) and the basic version of Montreal Cognitive Assessment scores increased by 2.38 (0.58) at week 12 compared with baseline levels, indicating improved cognitive function. Moreover, the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36. There were no significant differences in altered amyloid or tau deposition among the three arms, but hippocampal volume shrank less in the medium-dose arm to some extent.

Conclusions: Intranasal administration of ahaMSCs-Exos was safe and well tolerated, and a dose of at least 4×10⁸ particles could be selected for further clinical trials.

Trial registration number: NCT04388982.

Keywords: Neurocognitive Disorders.

Figure 1

Study design of the clinical trial. n=3−18 (theoretically). DLT, dose-limited toxicity.

Figure 2

Flowchart and specific visits for each participant. ECG, electrocardiogram;PET, positron emission tomography.

Figure 3

The inclusion, exclusion and withdrawal of the enrolled participants. MMSE, Mini-Mental State Examination; PET, positron emission tomography.

Figure 4

Safety evaluations of the intranasal ahaMSCs-Exos administration. (A) Blood pressure of each subject at baseline and 24 interventions (systolic and diastolic blood pressures); (B) heart rates of each subject at baseline and 24 interventions with a normal range of 60–100 beats per minute (bpm); (C) IgE levels; (D,E) laboratory indicators for liver function: alanine transaminase (ALT) and aspartate aminotransferase (AST); (F,G) laboratory indicators for renal function: blood urea nitrogen (BUN) and serum creatinine (Scr). (C–G) The indicators level at baseline, during the intervention period and 4 weeks after intervention. ahaMSCs-Exos, allogenic human adipose mesenchymal stem cells-secreted exosomes.

Figure 5

Changes in scores of scales from baseline to week 12. (A–C) Cognition examination scales: Alzheimer’s Disease Assessment Scale–Cognitive section (ADAS-cog), the Mini-Mental State Examination (MMSE) and the basic version of Montreal Cognitive Assessment (MoCA-B). (D) The Neuropsychiatric Inventory Scale (NPI). (E) The Geriatric Depression Scale (GDS). (F) Assessments of daily living activities: the scale of Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL), the Activities of Daily Living Scale (ADL) and the Instrumental Activities of Daily Living Scale (IADL).

Figure 6

Changes of hallmarks of AD pathology (amyloid, tau, neurodegeneration) in the follow-up period compared with baseline. The violin plot of the amyloid deposition (A) and tau deposition (B) alterations after 1 year detected by PET-MRI, comparing with baseline. The selected regions of interest included the frontal cortex, parietal cortex, lateral temporal, precuneus, anterior cingulate cortex and posterior cingulate cortex for amyloid, whereas lateral parietal, lateral temporal, medial temporal, frontal, occipital cortex, precuneus and posterior cingulate cortex for tau. (C) Altered proportions of bilateral hippocampal volumes indicated less atrophy in the subjects who accepted medium-dose administration. AD, Alzheimer’s disease; MRI, magnetic resonance imaging; PET, positron emission tomography.