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

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

Disclosures

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

In This Article

Human Studies

A total of 2861 papers and 31 clinical trials detailing human studies were identified through electronic searches. Among them, 11 studies (9 clinical trials and 2 published studies) were included in this review (Figure 3).

Figure 3.

Schematic presentation of clinical studies selected in the present review. AD, Alzheimer's disease.

Completed Trials

An open-label phase I study demonstrated the safety of intracranial human umbilical cord blood-derived MSC (HUC-MSC) injections (Table 2).[59] Although that study (NCT01297218)[60] included only nine patients with probable Alzheimer's disease (according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association [NINCDS-ARDA]), patients were carefully selected to include those administered with HUC-MSC. In order to include only those patients with amyloid disorder, all patients were Pittsburg compound B PET (PiB PET) positive, and none had severe white matter hyperintensities found using fluid-attenuated inversion recovery (FLAIR) (periventricular white matter hyperintensities <10 mm and deep white matter hyperintensities <25 mm).[61] Three received low-dose (3.0 × 106 cells) and six received high-dose (6.0 × 106 cells) HUC-MSCs. Stem cells were injected using stereotactic surgery on both sides of the hippocampus and the right precuneus (the left precuneus was left untreated for comparison). Results showed that stereotactic injections of HUC-MSC were safely completed in all nine patients. No patients exhibited cerebral hemorrhages in brain computed tomography (CT) scans taken within 24 h after injection, and no adverse events were reported 12 weeks postinjection. The study's small sample size precluded statistical analysis of efficacy, but the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) scores from baseline to week 12 were numerically superior in the high-dose group (3.5 + 5.6) compared with the low-dose group (5.3 + 3.5). Similar trends were observed for the Mini-Mental State Examination (MMSE). In contrast, amyloid levels between the HUC-MSC-treated right precuneus and the untreated left precuneus did not differ in PiB PET. The same study group conducted a longer term safety and efficacy follow-up study of subjects that completed the phase I clinical trial (NCT01696591).[62] During this 24-month extended follow-up study, no significant adverse events were noted. Brain MRIs taken 24 months postinjections showed no structural abnormalities (e.g. tumors or subdural hemorrhages). This is the only published study that investigated both short-term and long-term safety of stem cell therapy for patients with Alzheimer's disease. Utilizing stereotactic surgery to administer stem cells is recommended for future Alzheimer's disease studies using intra-cerebral stem cell injections.

Ongoing Clinical Trials

Nine human clinical trials [one open-label, one single-blind, and six randomized double-blind placebo-controlled trials (RDB-PCT)] are ongoing to investigate stem cell therapy for patients with Alzheimer's disease. All open and single-blind studies are aimed primarily at illustrating the safety of stem cell therapy for Alzheimer's disease. The first open-label study (NCT01547689) using HUC-MSCs was initially scheduled to end in December 2016.[63] However, the results are neither published nor reported, and the trial status is unknown. The second open-label study, starting in 2019 (NCT03297177),[64] plans to investigate longer term safety (6 months to 5 years) of autologous stem cells in patients with various neurological disorders including Alzheimer's disease. In addition, a single-blind, crossover, phase IIa study comparing MSC to a placebo in patients with mild-to-moderate Alzheimer's disease is actively ongoing.[65]

With respect to RDB-PCTs, the first study uses autologous adipose tissue-derived MSCs (NCT03117738).[66] In this phase I/II study, scheduled to end in June 2019, patients with mild-to-moderate Alzheimer's disease receive either autologous MSCs or intravenous placebo nine times with a 2-week interval. The primary outcome measure is the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) pre and 32 weeks postinjection. Other neuropsychiatric measures and diverse biomarkers including MRI, serum Aβ-40 and Aβ-42, amyloid precursor protein intracellular domain (AICD), and soluble neuregulin-1 (sNRG-1) will be compared as secondary outcome measures.

A 48-week, phase I/II study (NCT02899091) investigating the safety and tolerability of treatment using a placenta-derived MSC cell called CB-AC-02 was initially scheduled to end in June 2018.[67] This two-staged study aimed to enroll 24 participants and compare number of adverse events, neuropsychiatric measures, and Alzheimer's disease-related biomarkers between groups administered a placebo and placenta-derived MSCs; however, the study has no published results and its current status is unclear. Another phase I/II study (NCT02672306) using HUC-MSC or intravenous placebo was initially scheduled to end in October 2018.[68] The study planned to enroll 40 subjects with mild-to-moderate Alzheimer's disease, but only 16 subjects were enrolled as of April 2018. The study currently is active but not recruiting, so it is unknown if it will be extended past the initial end date.

A phase I trial (NCT02600130) studying the safety and efficacy of human MSCs called Longeveron Mesenchymal Stem Cells (LMSC) has been ongoing since August 2016.[68] In this actively recruiting study, 25 subjects with Alzheimer's disease will be randomly chosen to receive low-dose LMSCs (20 × 10[6] cells), high-dose LMSCs (100 × 10[6] cells), or a placebo with a 2 : 2:1 ratio. Subjects will be reexamined at 2, 4, 13, 26, 39, and 52 weeks for adverse events, neuropsychological tests, blood samples, cerebrospinal fluid (CSF) studies, and MRIs.

The last two studies, conducted by the same group, are actively ongoing and recruiting. In the first study (NCT02054208), 45 subjects with Alzheimer's disease will be randomly placed into three groups: low-dose HUC-MSC (1 × 10^7 cells/2 ml), high-dose HUC-MSC (3 × 10^7 cells/2 ml), and placebo (isotonic saline, 2 ml).[70] The last two studies, conducted by the same group, are actively ongoing and recruiting. In the first study (NCT02054208), 45 subjects with Alzheimer's disease will be randomly placed into three groups: low-dose HUC-MSC (1 × 10^7 cells/2 ml), high-dose HUC-MSC (3 × 10^7 cells/2 ml), and placebo (normal saline, 2 ml).[71] The study was divided into two stages: stage 1 includes 9 subjects (3 subjects receiving a low dose and 6 subjects receiving a high dose) and stage 2 includes 36 subjects (24 subjects receiving a high dose and 12 subjects receiving a placebo). The last study (NCT03172117) is a follow-up study of safety and efficacy in subjects who completed NCT02054208.[72] The study was divided into 2 stages: stage 1 includes 9 subjects (3 subjects receiving a low dose and 6 subjects receiving a high dose) and stage 2 includes 36 subjects (24 subjects receiving a high dose and 12 subjects receiving a placebo). The last study (NCT03172117) is a follow-up study of safety and efficacy in subjects who completed NCT02054208 (Table 3).

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....