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.

Stem Cells Build “Biobridges” to Aid Brain Repair


University of South Florida (USF) scientists have suggested a new strategy for stem cell-mediated brain repair following trauma.

In several preclinical experiments, the USF group found that transplanted stem cells build a “biobridge” that links an injured site in the brain to a site where neural stem cells form.

Principal investigator, Cesar Borlongan, professor and director of the USF Center for Aging and Brain Repair, said: “The transplanted stem cells serve as migratory cues for the brain’s own neurogenic cells, guiding the exodus of these formed host cells from their neurogenic niche towards the injured brain.”

Cesar Borlongan
Cesar Borlongan

On the strength of these preclinial studies in laboratory animals, the US Food and Drug Administration recently approved a limited clinical trial to transplant SanBio Inc.’s SB632 cells into patients with traumatic brain injuries. SB632 cells are a proprietary product of SanBio, Inc., and SB632 cells are derived from mesenchymal stem cells but they have been genetically engineered to express the intracellular domain of the Notch protein (NICD; see C. Tate, et al., Cell Transplantation, Vol. 19, pp. 973–984, 2010). If the Notch protein, which functions as a signaling protein and normally sits in the cell membrane, has its outer piece removed, the protein is constitutively activated. This full-time activation of the Notch protein and its downstream targets drive SB632 cells to form neural cells; something that mesenchymal stem cells typically do not readily make.

The Notch pathway. Notch is synthesised as a precursor protein that is processed by a furin-like convertase (S1 cleavage) in the Golgi before being transported to the cell surface, where it resides as a heterodimer. Interaction of Notch receptors with Notch ligands, such as Delta-like or Jagged, between two bordering cells leads to a cascade of proteolytic cleavages. The first cleavage (S2 cleavage) is mediated by ADAM-family metalloproteases such as ADAM10 or TNF-alpha-converting enzyme (TACE, also known as ADAM17), generating a substrate for S3 cleavage by the gamma-secretase complex. This cleavage releases the Notch intracellular domain (NICD) from the cell membrane. NICD then translocates to the nucleus, where it interacts with the DNA-binding protein RBP-Jkappa (also known as CBF1) and cooperates with Mastermind to displace corepressor proteins, thus activating the transcription of Notch target genes. The basic helix-loop-helix proteins hairy/enhancer of split (such as Hes1, 5 and 7) and Hes-related proteins (Hey1, 2 and L) and EphrinB2 are the best characterised downstream targets. Blockade of Notch signalling has been achieved by using different strategies, including (A) anti-DLL4 monoclonal antibodies, (B) gamma-secretase inhibitors such as DBZ and DAPT, (C) soluble DLL4-Fc, (D) anti-Notch1 neutralising antibodies, and (E) Notch1-trap.
The Notch pathway. Notch is synthesised as a precursor protein that is processed by a furin-like convertase (S1 cleavage) in the Golgi before being transported to the cell surface, where it resides as a heterodimer. Interaction of Notch receptors with Notch ligands, such as Delta-like or Jagged, between two bordering cells leads to a cascade of proteolytic cleavages. The first cleavage (S2 cleavage) is mediated by ADAM-family metalloproteases such as ADAM10 or TNF-alpha-converting enzyme (TACE, also known as ADAM17), generating a substrate for S3 cleavage by the gamma-secretase complex. This cleavage releases the Notch intracellular domain (NICD) from the cell membrane. NICD then translocates to the nucleus, where it interacts with the DNA-binding protein RBP-Jkappa (also known as CBF1) and cooperates with Mastermind to displace corepressor proteins, thus activating the transcription of Notch target genes. The basic helix-loop-helix proteins hairy/enhancer of split (such as Hes1, 5 and 7) and Hes-related proteins (Hey1, 2 and L) and EphrinB2 are the best characterised downstream targets. Blockade of Notch signalling has been achieved by using different strategies, including (A) anti-DLL4 monoclonal antibodies, (B) gamma-secretase inhibitors such as DBZ and DAPT, (C) soluble DLL4-Fc, (D) anti-Notch1 neutralising antibodies, and (E) Notch1-trap.

While this over-simplifies the field to some extent, there are two views on how stem cells heal brain damage caused by injury or neurodegenerative disorders. One view postulates that stem cells implanted into the brain directly replace dead or dying cells by differentiating into neurons and glial cells. The other view is that transplanted stem cells secrete growth factors that indirectly rescue the injured tissue. This present USF study argues for a third view, namely that implanted stem cells for a causeway in the brain between damaged areas and those anatomical structures that give birth to neural stem cells.

In this USF study, Borlongan and his group randomly assigned rats with traumatic brain injury and confirmed neurological impairment to one of two groups. The first group received transplants of SB632 cells into the region of the brain affected by traumatic injury. The second group received a sham procedure in which solution alone was infused into the brain with no implantation of stem cells.

At one and three months post-TBI (traumatic brain injury), the rats that had received SB632 transplants showed significantly better motor and neurological function and reduced brain tissue damage when compared to rats that had received no stem cells. These robust improvements despite the fact that the transplanted stem cells showed fair to poor survival that diminished over time.

Next, Borlongan’s laboratory workers examined the brain tissue of these rats. At three months post-TBI, the brains of transplanted rats showed massive cell proliferation and differentiation of stem cells into neuron-like cells in the area of injury. This was accompanied by a solid stream of stem cells that had migrated from the brain’s uninjured subventricular zone (where many new stem cells are formed) to the brain’s site of injury.

In contrast, those rats that had received solution alone showed limited proliferation and neural-commitment of stem cells, and only showed scattered migration to the site of brain injury and almost no expression of newly formed cells in the subventricular zone. Thus, without the addition of transplanted stem cells, the brain’s self-repair process appeared insufficient to mount a defense against the cascade of TBI-induced cell death.

Borlongan concluded that the transplanted stem cells create a neurovascular matrix that bridges the gap between the region in the brain where host neural stem cells arise and the site of injury. This pathway, or “biobridge,” ferries the newly emerging host cells to the specific place in the brain in need of repair, and helps them to promote functional recovery from traumatic brain injury.

A Stem Cell Treatment for Stroke


A new clinical trial is enrolling people who are dealing with the disabling effects of stroke.

Every year approximately 800,000 Americans suffer a stroke. Strokes or TIAs for “trans-ischemic attacks” result from blockage of a blood vessel in the brain. The lack of blood flow to the brain results in the death of those cells that starve from oxygen, and the aftermath of a stroke is remarkably unpleasant; long-term disability, permanent brain damage, and even death. Stroke is the leading cause of adult disability and extracts an annual burden of $62 billion on the US economy. Physical therapy can improve the deficits caused by a stroke, but there are, to date, no good treatments to ameliorate the condition of a stroke patient.

In the hopes of creating new options for stroke patients, researchers at Northwestern Medicine are examining a new regenerative treatment for stroke that utilizes a novel stem cell line called SB623. This stem cell line might provide increased motor function to stroke victims.

Northwestern is only one of three sites in the nation enrolling patients in a clinical study to evaluate the efficacy and safety of adult stem cell therapy in stroke patients. Patient who have suffered from so-called “ischemic stroke” suffer from impaired bodily functions that includes such conditions as paralysis, weakness on one side, difficulty with speech and language, vision issues, and cognitive deficits.

Joshua Rosenow, the principal investigator of this clinical trial, is the director of Functional Neurosurgery at Northwestern Memorial Hospital. Rosenow had this to say of this clinical study: “Two million brain cells die each minute during a stroke making it critical to get treatment fast at the earliest sign of symptoms once brain damage occurs, there’s very little that can be done medically to reverse it. While this study is only a preliminary step towards understanding the healing potential of these cells, we are excited about what a successful trial could do for a patient population that hs very limited therapeutic options.”

The primary purpose of this study is to examine the safety of SB623 stem cells. However, there is an added motive behind this study, and that is to determine if SB623 cells are efficacious as a treatment for stroke patients. SB623 cells are genetically engineered mesenchymal stem cells from adult bone marrow.

Richard Bernstein, the director of Northwestern Memorial’s Stroke Center, weighed in: “Although not proven in humans, these stem cells (SB623) have been shown to promote healing and improve function when administered in animal models of stable stroke. The cells did not replace the neurons destroyed by stroke, but instead they appeared to encourage the brain to heal itself and promote the body’s natural regenerative process. Eventually, the implanted stem cells disappeared.”

Rosenow added, “In this study, the cells are transplanted into the brain using brain mapping technology and scans, allowing us to precisely deposit the cells in the brain adjacent to the area damaged by the stroke.”

The first participants have received injections of 25 million cells, but as the study progresses, the dose will escalate to 5 million and eventually 10 million cells. Since SB623 cells are allogeneic, which is to say that they come from someone other than the patient, a single donor’s cells can be used to treat as many other patients. All subjects in this study will be followed for up to two years with periodic evaluations for safety and effectiveness in improving motor function.

Bernstein explained, “Stroke can be a very disabling and life-changing event. Even just a slight improvement in function could make a huge difference for a person impacted [sic] by stroke. To potentially regain movement or speech is a very exciting prospect. In the animal models, the improvements appeared to remain even after the implanted stem cells disappeared.

Even at this early stage in this clinical trial, there is a great deal of excitement over the potential for stem cell therapy. Rosenow echoed this excitement when he said, “Of these cells are proven effective in improving, or even reversing brain damage, the implications of a successful outcome reach far beyond just stroke. Stem cell therapy may hold the key to treating a wide range of neurological disorders that do not have many available therapies. The Northwestern team is very excited to be a part of this groundbreaking trial.”

Participants for this trial must be between the ages of 18 and 75 years old, must have had an ischemic stroke in the last six to 36 months. They should have moderate to severe symptoms with impaired motor function. Full inclusion and exclusion criteria are available online. Full inclusion and exclusion criteria are available online. The FDA-approved phase 1-11 study is expected to enroll 18 subjects nationwide and this study is slated to last up to two years.

Other sites participating in the trial are the University of Pittsburgh Medical Center and Stanford University School of Medicine. The trial is funded by SanBio, Inc., a regenerative medicine company that developed the SB623 stem cell line.

SB623 papers:

1. Extracellular matrix produced by bone marrow stromal cells and by their derivative, SB623 cells, supports neural cell growth.  Aizman I, Tate CC, McGrogan M, Case CC.

  • J Neurosci Res. 2009, 87(14):3198-206.

2. Notch-induced rat and human bone marrow stromal cell grafts reduce ischemic cell loss and ameliorate behavioral deficits in chronic stroke animals. Yasuhara T, Matsukawa N, Hara K, Maki M, Ali MM, Yu SJ, Bae E, Yu G, Xu L, McGrogan M, Bankiewicz K, Case C, Borlongan CV.  Stem Cells Dev. 2009, 18(10):1501-14

3. Reversal of dopaminergic degeneration in a parkinsonian rat following micrografting of human bone marrow-derived neural progenitors. Glavaski-Joksimovic A, Virag T, Chang QA, West NC, Mangatu TA, McGrogan MP, Dugich-Djordjevic M, Bohn MC.  Cell Transplant. 2009, 18(7):801-14.

4.

Tate CC, Fonck C, McGrogan M, Case CC. Cell Transplant. 2010,19(8):973-84.

5. Glial cell line-derived neurotrophic factor-secreting genetically modified human bone marrow-derived mesenchymal stem cells promote recovery in a rat model of Parkinson’s disease.  Glavaski-Joksimovic A, Virag T, Mangatu TA, McGrogan M, Wang XS, Bohn MC. J Neurosci Res. 2010, 88(12):2669-81.

6. Comparing the immunosuppressive potency of naive marrow stromal cells and Notch-transfected marrow stromal cells.

  • Dao MA, Tate CC, Aizman I, McGrogan M, Case CC.

J Neuroinflammation. 2011, 8(1):133.

7.

Tate CC and Case CC.

  • Chapter in “Neurological Disorders”, InTech, 2012.