Plant Polyphenol May Help Improve Wound Healing By Activating Mesenchymal Stem Cells

Akito Maeda and his coworkers from Osaka University in Osaka, Japan have discovered that a plant-based polyphenol promotes the migration of mesenchymal stem cells (MSCs) in blood circulation. This same plant polyphenol also causes MSCs to accumulate in damaged tissues and improve wound healing.

This compound, cinnamtannin B-1, might be a candidate drug for stem cell treatments for cutaneous disorders associated with particular diseases and lesions.

Cinnamtannin B-1
Cinnamtannin B-1

Cinnamtannin B-1, a flavonoid, seems to activate membrane-bound enzymes; specifically the Phosphatidylinositol-3-kinase enzyme, which is an integral enzyme in the phosphoinositol signal transduction pathway, which culminates in the mobilization of intracellular calcium stores and profoundly alters cell behavior and function.

Phosphoinositol pathway signaling

Flow cytometry analysis of mouse blood established that administration of cinnamtannin B-1 increased the release of MSCs from bone marrow. Laboratory experiments with cultured MSCs showed that cinnamtannin B-1 treatment activated MSC migration and recruitment to wounds. This seems to suggest that the enhanced healing caused by cinnamtannin B-1 treatment is due to enhanced MSC migration and homing to damaged tissues.

Imaging analysis of whole animals that had MSCs that expressed the firefly luciferase enzyme showed that cinnamtannin B-1 treatment increased the homing of MSCs to wounds and accelerated healing in a diabetic mouse model.

When Maeda and his colleagues treated MSCs with small molecules that inhibited phosphatidylinositol-3-kinase, those cells no longer responded to cinnamtannin B-1, which confirms the role of the phosphoinositol signal transduction pathway in cinnamtannin B-1 activation of MSCs.

Thus, cinnamtannin B-1 promotes MSC migration in culture and accelerates wound healing in mice. In addition, cinnamtannin B-1-induced migration of MSCs seems to be mediated by specific signaling pathways.

SanBio, Inc Moves Forward With Clinical Stem Cell Trial for Traumatic Brain Injury in Japan

Traumatic brain injuries can result from a variety of causes, ranging from car accidents, falls, occupational hazards, and sports injuries. The cause of traumatic brain injury (TBI) differs from that of ischemic stroke, but many of the clinical manifestations are somewhat similar (motor deficits). Such injuries can cause lifelong motor deficits, and there are currently no approved medicines for the treatment of persistent disability from traumatic brain injury.

SanBio, Inc., has completed the regulatory requirements to conduct a clinical trial using their proprietary SB623 regenerative cell therapy to treat patients who suffer from TBI. The obligatory 30-day review period of clinical trial notification by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was completed on March 7, 2016. No safety concerns were voiced, and the trial can proceed.

SanBio’s clinical trial is entitled “Stem cell therapy for traumatic brain injury” or STEMTRA, and it will study the safety and efficacy of SB623 cell therapy in treating patients who suffer from chronic motor impairments following a TBI.

Enrollment in this clinical trial started in the United States in October, 2015. The trial will include clinical sites and patients in Japan and will enroll ~52 patients. The enrollment of Japanese patients is expected to accelerate the overall enrollment of human subjects.

SanBio spokesperson, Damien Bates, the Chief Medical Officer and Head of Medical Research at SanBio, said: “SanBio’s regenerative cell medicine, SB623, has improved outcomes in patients with persistent motor deficits due to ischemic stroke, and our preclinical data suggest that it may also help TBI patients.  This is the first global Phase 2 clinical trial for TBI allogeneic stem cells, and the approval to conduct the trial in Japan, as well as in the United States, brings us one step closer to determining SB623’s efficacy for treatment whose who suffer from the effects of traumatic brain injury.”

SB623 are modified mesenchymal stem cells that transiently express a modified human Notch1 gene that only contains the intracellular domain of the Notch1 protein. This activated gene drives mesenchymal stem cells to form a cell type that habitually supports neural cells and promotes their health, survival, and healing.  When administered into damaged neural tissue, SB623 reverses neural damage. Since SB623 cells are allogeneic (from a donor), a single donor’s cells can be used to treat many patients. In cell culture and animal models, SB623 cells restore function to damaged neurons associated with stroke, traumatic brain injury, retinal diseases, and Parkinson’s disease. SB623 cells function by promoting the body’s natural regenerative process.

SanBio recently completed a US-based Phase 1/2a clinical trial for SB623 in patients with chronic motor impairments six months to five years following an ischemic stroke. The results of this trial demonstrated that SB623 can improve motor function following a stroke. On the strength of these results, SanBio initiated a Phase 2b randomized, double-blind, clinical trial of 156 subjects began enrollment in December 2015.  This trial is entitled ACTIsSIMA (“Allogeneic Cell Therapy for Ischemic Stroke to Improve Motor Abilities”).

Since the therapeutic mechanism of action of SB623 cells and the proposed route of administration are similar in the two trials (the stroke and TBI trials), the results of the TBI trial should be similar to those of the stroke trial.

The Japanese regulatory agencies grant marketing approval for regenerative medicines earlier countries as a result of an amendment to the Pharmaceutical Affairs Law in 2014. This particular amendment defined regenerative medicine products as a new category in addition to conventional drugs and medical devices, and the conditional and term-limited accelerated approval system for regenerative medicine products has started.

Two regenerative medicine products have already gained marketing approval under this new system, and the government-led industrialization of regenerative medicine products has gradually been realized.

SanBio has begun the preparation of clinical trial facilities in Japan and expects the launch of the clinical trial in 2016. the company hopes to market the medicine in Japan by taking advantage of the accelerated approval system.