Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: a phase I clinical trial

Abstract

Backgrounds: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies.

Objectives: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs).

Methods: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 10⁷ cells/2 mL), and six patients received a high dose (3.0 × 10⁷ cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study.

Results: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed.

Conclusions: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy.

Trial registration: ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.

Keywords: Alzheimer’s disease; Intracerebroventricular injection; Mesenchymal stem cell; Phase I/IIa.

Fig. 1

Study flow diagram for a phase I protocol in participants with Alzheimer’s disease. A Participants underwent three repeated hUCB-MSC injections in a dose-escalating, open-label fashion with two sequential doses (1.0 × 10⁷ cells/2 mL in the low dose [LD] group and 3.0 × 10⁷ cells/2 mL in the high dose [HD] group). Before continuing the study with subsequent participants, we confirmed that there was no DLT. Empty arrows indicate hUCB-MSC injection. B Schematic drawing of right intracerebroventricular injection of hUCB-MSCs via the Ommaya reservoir

Fig. 2

White blood cell count (A), Alzheimer’s disease biomarkers (B), and MSC-related markers (C) in the cerebrospinal fluid. Bars indicate standard error. WBC, white blood cell; sICAM-1, soluble intercellular adhesion molecule-1; GDS-15, growth differentiation factor 15