Commentary on "Safety and efficacy of human umbilical cord-derived mesenchymal stem cells in patients with Alzheimer’s disease: study protocol for an open-label self-control trial"

In spite of the significant progress achieved in the medical field in the past decades, neurological illnesses remain as one of the leading causes of disease burden in the world.In the next years, with the progressive ageing of the population, the prevalence of these diseases and the expenses associated with them are expected to increase even more.Contemporary treatments such as pharmacological agents are restricted in their potential to improve neurological function and are unable to promote restoration of lost neurons and other brain cells damaged in such diseases. Stem cell transplantation, initially developed more than 40 years ago to treat hematological malignant disorder, has more recently demonstrated promising results in different ailments, including autoimmune, cardiovascular, and neurological diseases(Rosado-de-Castro et al., 2014).

Alzheimer's disease (AD) is one of the most prevalent dementias, which is characterized by the deposition of extracellular amyloid-beta protein (Aβ) and the formation of neurofibrillary tangles within neurons (Yang et al., 2013).The majority of AD patients develop inflammatory plaques,neurofibrillary tangles, and neurodegenerative symptoms.At this stage, an effective method to treat patients with AD is to block Aβ deposition, increase cell survival rate and supplement the lost cells (Parekkadan and Milwid, 2010).Stem cell replacement therapy has come into the spotlight.Its mechanism of action is to infuse healthy stem cells into a patient’s body which then repair or replace injured cells or tissues.

Human umbilical cord-derived mesenchymal stem cells(hUC-MSCs) have recently become an area of interest in stem cell replacement therapy for neurodegenerative diseases. hUC-MSCs are a kind of stem cells derived from the umbilical cord and perivascular tissue.

Under certain induction conditions, hUC-MSCs can differentiate into fibroblasts, adipose cells, chondrocytes,myocytes, vascular endothelial cells, neurons and glial cells,and they can also express neurotrophic factors, vascular endothelial growth factors, brain-derived neurotrophic factors and glial cell line-derived neurotrophic factors (Wang et al.,2004), which bring new hope to AD treatment. Recent animal experiments have demonstrated that intracerebroventricular administration of hUC-MSCs can improve learning and memory abilities in mouse models of AD induced by chemical (dgalactose and aluminum chloride) and physical injuries (Ma et al., 2012). Intravenous administration of hUC-MSCs can greatly improve learning and memory abilities and postpone ageing in amyloid precursor protein transgenic mouse models of AD, possibly through regulating the expression of senescence-related associated genes p21, p53, silence information regulator 2 and proliferating cell nuclear antigen (Cui et al., 2015).

However, these different approaches are not easily translated to the clinic. Given this, a developing strategy involves cell therapy with the transplantation of bone marrow-derived cells or other cell types. Cell therapy has been used in different animal models of neurological diseases and lesions with interesting results and it is beginning to be used in clinical trials. Interestingly, data from clinical studies suggests that an intravitreal injection of autologous bone marrow-derived cells is technically feasible and safe(Zaverucha-do-Valle et al., 2014).

Studies are needed to further investigate the safety and efficacy of hUC-MSCs transplantation for AD treatment in the clinic.

In this article, the authors properly choose the prospective self-control, phase I/II clinical trial to validate the safety(primary outcome) and efficacy (secondary outcome) of hUC-MSCs transplantation for AD treatment in the clinic which is both timely and relevant for neurologists who desires to improve patient outcomes through cell therapy(Niu et al., 2016).

For isolation, culture and sub-culture of hUC-MSCs,umbilical cords will be harvested from 18–48-year-old healthy pregnant women who will have a normal delivery and will agree to sign the informed consent.

The trial will include an effective group of 30 patients with moderate to severe AD. It is important to point out that prior to the clinical trial, cell quality will be ensured:(1) Adherence to plastics in standard culture conditions;(2) phenotype: CD105, CD73, CD90 positive (≥ 95%);CD45, CD34, CD14 or CD11b, CD79a or CD19, HLA-DR negative (≤ 2%); (3)in vitrodifferentiation: osteoblasts,adipocytes, chondroblasts (demonstrated by staining ofin vitrocell culture; (4) by a sterility test (negative result); and(5) by an endotoxin test (negative result).

Park et al. (2016) have recently suggested that single intravenously administered hUCB-MSCs are not delivered to the brain and also do not have a significant influence on AD pathology. Differently, Ehrhart et al. (2016) studied human umbilical cord blood cells (hUCBCs) and showed that hUCBCs were broadly detected both in the brain and several peripheral organs, including the liver, kidney, and bone marrow, starting within 7 days and continuing up to 30 days posttransplantation. In their study, no hUCBCs were recovered in the peripheral circulation, even at 24 hours posttransplantation, and hUCBCs reached several tissues including the braiz following a single intravenous treatment, suggesting that this route can be a viable method of administration of these cells for the treatment of neurodegenerative diseases.

In Niu et al. (2016) study, the treatment will be carried out by intravenous injection for eight times, once every 2 weeks in the 1stmonth of each quarter. Patients will be asked to lie in a supine position and hUC-MSCs will be administeredviathe peripheral vein using a transfusion apparatus. In total, 30 mL of hUC-MSC suspension will be controlled to drip completely within 10 minutes and then 10 mL of 0.9%sodium chloride solution will be used to flush the catheter.At the end of the first infusion, headache, dizziness, nausea and vomiting, jerks, and fever will be monitored. Once any of these occurs, date of symptom presence, management method and the possible relationship with treatment should be recorded in detail.

Safety and efficacy evaluation proposed in this study are adequate. Primary outcomes (safety) will be evaluated by:(1) Number of participants who have adverse events within 10 weeks after the last infusion of hUM-MSCs; and (2)number of participants who have adverse events within 1 year of follow up. Secondary outcomes (efficacy) will be evaluated by: Improvement of AD 10 weeks after the last infusion of hUM-MSCs.

A rigorous statistical analysis of all data will be carried out and the trial will be performed in accordance to the World Medical Association’sDeclaration of Helsinki.

Authors have previously performed a series of studies on hUC-MSCs:in vitroexperiments as the culture, preservation, and differentiation of hUC-MSCs; proliferation of hematologic malignant tumor cells when co-cultured with hUC-MSCs; as well as the effects of MSCs on immunological responses of Sprague-Dawley rats after skin radiation injury. In terms of AD, the results from C57 mice with acute AD have confirmed the efficacy and safety of hUC-MSCs in animal experiments.

Overall, this protocol for phase I/II clinical trials proposed by Niu et al. (2016) is a valuable contribution to the neurological field of AD. Its results will aid to evaluate new possibilities to clinical AD treatment using the potential hUC-MSC replacement therapy.

Bianca Gutfilen＊, Gianluca Valentini

Department of Radiology, Universidade Federal do Rio de Janeiro, Hospital Universitário Clementino Fraga Filho,Rio de Janeiro, RJ, Brazil (Gutfilen B)

Advanced Center Oncology Macerata (ACOM), Località Cavallino, Montecosaro, Italy (Valentini G)

orcid: 0000-0001-8632-7474 (Bianca Gutfilen)

How to cite this article: Gutfilen B, Valentini G (2016) Commentary on "Safety and efficacy of human umbilical cord-derived mesenchymal stem cells in patients with Alzheimer’s disease:study protocol for an open-label self-control trial." Clin Transl Degener Dis 1(2):84-85.

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Ehrhart J, Darlington D, Kuzmin-Nichols N, Sanberg CD, Sawmiller DR, Sanberg PR, Tan J (2016) Biodistribution of infused human umbilical cord blood cells in Alzheimer's Disease-like murine model. Cell Transplant 25:195-199.

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