Source: Ruijin Hospital

Recently, Professor Wang Gang's team of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine completed and released the international first Clinical Trial of intranasal treatment of Alzheimer's disease using exosome derived from mesenchymal stem cells (Clinical Trial NCT04388982), the research results were published in General Psychiatry. The paper is titled "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 ".

Alzheimer's disease (AD) is the most common neurodegenerative disease and the most common cause of dementia, and there is no effective cure at present, making it a major health killer threatening the quality of life of the elderly. Exosomes are extracellular vesicles released by cells in resting or stressed states and are rich in lipids, proteins and nucleic acids. They can be delivered to distant regions by body fluids and taken up by target cells through three pathways: membrane fusion, endocytosis, and ligand-receptor mediated mechanisms. In recent years, exosomes have been found to play an important role in the occurrence and development of AD, providing new possibilities for the diagnosis or treatment of AD. In particular, exosomes derived from Mesenchymal stem cells (MSCs), compared with MSCs, have the advantages of low immunogenicity, easy availability (batch synthesis from commercially available cell lines), no invasive operation during collection or differentiation, and easy storage, making them possible for clinical application. Previous studies by the collaborative team showed that intranasal administration of human adipose-derived mesenchymal stem cell exosomes (ahaMSC-Exos) from healthy volunteers improved the pathological status and spatial memory of AD in a mouse model.

In order to explore the Clinical application and therapeutic possibilities of ahaMSC-Exos, Professor Wang Gang's team conducted the first international clinical Trial of exosome intranasal treatment of AD (Clinical Trial NCT04388982) to verify the safety and effectiveness of intranasal administration of AhamSC-exos in AD patients. The study was an open-label clinical trial divided into three dose groups: The low dose group (2×108), medium dose group (4×108) and high dose group (8×108) were selected by the "3+3" trial design, and qualified subjects were assigned to different dose groups successively. The intervention period lasted for 12 weeks, with intranasal administration twice a week. Follow-up at the end of treatment included weeks 12, 16, 24, 36 and 48. The study found that no adverse events were reported in all subjects, and there were no significant abnormalities in safety assessment indicators (including biochemical tests). Compared to baseline, participants in the moderate-dose group had a 2.33 (1.19) decrease in ADAS-cog scores at week 12 and a 2.38 (0.58) increase in MoCA-B scores, indicating an improvement in cognitive function. In addition, ADAS-cog scores in the moderate-dose group continued to decline by 3.98 points through week 36. Tracer-specific PET-MRI showed no significant difference in amyloid or tau deposition changes among the three dose groups, but hippocampal atrophy was less severe in the medium-dose group. The clinical trial demonstrated the safety of ahaMSC-Exos, with all subjects tolerating intranasal administration twice a week, while providing a dose selection and reference for further clinical trials.

It is reported that this trial is the first international attempt to apply exosomes secreted by MSCs to the clinical treatment of AD, which brings hope for the treatment of AD. The results suggest that ahaMSCs-Exos is safe for intranasal administration in the treatment of AD, and at least 4×10^8 doses should be selected for larger multicenter clinical trials.

The corresponding author of the study is Professor Wang Gang, Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and co-corresponding authors are Researcher Gao Xiaoling, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, and Deputy chief physician Ren Rujing, Ruijin Hospital. Dr. Xie Xinyi from Ruijin Hospital, Dr. Song Qingqing from the Department of Pharmacology and Chemical Biology, Dr. Dai Chengxiang from Sibiman Biotechnology Co., LTD., and Dr. Cui Shishuang from Ruijin Hospital are co-first authors. Professor Chen Shengdi from Ruijin Hospital and Professor Chen Hongzhuan from Shanghai University of Traditional Chinese Medicine gave important guidance to this study.