Stemedica Cell Technologies Press Release
The San Diego stem cell company Stemedica Cell Technologies, Inc reported treatment of its first patient as part of a 35 patient clinical trial in stroke patients. The study uses bone marrow stem cells that have been preconditioned with hypoxia and used in a non-matched manner. The trial is being conducted at the University of California San Diego and is titled “A Phase I/II, Multi-Center, Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of a Single Intravenous Dose of Allogeneic Mesenchymal Bone Marrow Cells to Subjects with Ischemic Stroke.”
Every year more than 800,000 Americans suffer a stroke. According to the American Heart Association, stroke is the fourth leading cause of death – costing an estimated $73.7 billion in 2010 for stroke-related medical costs and disability.
The study’s Principle investigator is Michael Levy, MD, PhD, FACS, chief of pediatric neurosurgery at Children’s Hospital San Diego (CHSD) and professor of neurological surgery at UCSD. The aim of the trial is to determine tolerance and therapeutic outcomes for intravenously-delivered adult allogeneic mesenchymal stem cells and to hopefully pave the way for a new therapeutic category of treatment for ischemic stroke. When asked about the first patient in the study, Dr. Levy said, “The treatment went smoothly; no side effects were observed, and the patient was released from the hospital the next day.”
Lev Verkh, PhD, Stemedica’s chief regulatory and clinical development officer, commented: “Many years of research and hard work by the Stemedica team culminated today in the treatment of the first patient using our uniquely designed stem cells to be effective under ischemic condition. We are proud to be the first company to initiate a study such as this under a clinical protocol approved by the U.S. Food and Drug Administration (FDA).”
Several companies are using stem cells for stroke. For example the company Aldagen is using bone marrow derived cells from the same patient. Their approach involves bone marrow extraction, purification of a selected stem cell from the bone marrow, and subsequent administration of the cell into the patients. The reason why stroke is of great interest to many companies is because recent studies have demonstrated that the brain has its own stem cells that start multiplying after a stroke. Unfortunately these stem cells that are already existing are not found in a high enough number to cause a substantial repair. The idea is that when new stem cells are added, they assist the existing stem cells in supporting the repair process.
“This clinical trial marks a significant achievement in the treatment of debilitating ischemia-related pathologies including ischemic stroke,” said Nikolai Tankovich, MD, PhD, president and chief medical officer of Stemedica. “We believe these specially designed mesenchymal stem cells are able to tolerate, survive and repair ischemic tissues caused by an infarction of the brain, heart, kidney, retina and other organs. In addition, these mesenchymal stem cells are capable of up regulating an array of important genes that are essential for the synthesis of critical proteins involved in recovery.”
Dr. Verkh continued, “Patients in this study have significant functional or neurologic impairment that confines them to a wheelchair or requires home nursing care or assistance with the general activities of daily living and have received the ischemic stroke diagnosis at least six months prior to enrollment in this study”.
The inclusion/exclusion criteria are:
Inclusion Criteria:
•Clinical diagnosis of ischemic stroke for longer than 6 months
•Brain CT/MRI scan at initial diagnosis and at enrollment consistent with ischemic stroke
•No substantial improvement in neurologic or functional deficits for the 2 months prior to enrollment
•NIHSS score between 6-20
•Life expectancy greater than 12 months
•Prior to treatment patient received standard medical care for the secondary prevention of ischemic stroke
•Adequate organ function as defined by the following criteria:
Exclusion Criteria:
•History of uncontrolled seizure disorder
•History of cancer within the past 5 years.
•History of cerebral neoplasm
•Positive for hepatitis B, C or HIV
•Myocardial infarction withing six months of study entry
•Findings on baseline CT suggestive of subarachnoid or intracerebral hemorrhage within past 12 months.
•Allergies to Bovine or Porcine products
Stemedica Treats First Patient with Ischemic Allogeneic Mesenchymal Stem Cells
How Bone Marrow Stem Cells Help in Stroke Recovery
Nakano-Doi et al. Stem Cells 28(7):1292-302. May 2011
Scientists from the Institute for Advanced Medical Sciences of Hyogo, Japan have announced new research findings suggesting that bone marrow stem cells may be useful in the treatment of stroke. Although other scientists have previously demonstrated similar findings, including in patients, (Suárez-Monteagudo et al. Restor Neurol Neurosci. 2009;27(3):151-61), what is astonishing about the current work is that an actual biological mechanism by which the stem cells are functioning is proposed.
In the paper Nakano-Doi et al. Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction. Stem Cells 28(7):1292-302. May 2011, the scientists induced stroke in mice by tying up the middle cerebral artery. This causes damage to approximately the same area that gets damaged in humans who have a stroke. Two days after inducing this “artificial stroke”, the scientists injected the mice with 1 million bone marrow mononuclear cells (BMMC). These cells are the same cells that are used in bone marrow transplantation, they are not expanded or manipulated stem cells, just cells from the bone marrow that have been depleted of red blood cells. In other mice the scientists injected a control solution of phosphate buffered saline. All injections were performed intravenously.
The injected bone marrow cells were found to accumulate near the area of brain injury. Blood vessel cells, termed endothelial cells, were found to start multiplying near the area of injury in animals that received BMMC but not control animals. Multiplication of endothelial cells is viewed as a sign of new blood vessel formation, called “angiogenesis”. The process of angiogenesis is usually involved in healing of tissue, or generation of new tissue to replace damaged tissue. Thus this suggests that the stem cells from the BMMC may be triggering the cellular microenvironment surrounding the brain tissue to start proliferating.
Indeed if the BMMC are stimulating a repair process, the next question is whether the BMMC are themselves forming new neural tissue, or if they are producing factors that stimulate resident stem cells in the brain to produce new brain tissue. When the investigators assessed the multiplication of endogenous brain stem cells, they found that these cells started to multiply. Furthermore, they found that multiplication of the endogenous brain stem cells is actually dependent on angiogenesis. Specifically, when the angiogenesis blocking molecule endostatin was given to mice that had received BMMC, the endogenous brain stem cells did not multiple. Multiplication of these cells was associated with functional recovery of the animals as assessed by behavioural testing.
There are several “closed system” devices that allow for the harvesting of the bone marrow, isolation of BMMC and reimplantation. The fact that this study shows intravenous injection of BMMC induces some therapeutic benefit should trigger further investigations in the clinical setting. Previously it was required to have a fully equipped laboratory to perform such clinical trials. Now devices like Harvest Technology’s BMAC system, Arteriocyte’s Magellan System, or Bio-Met’s GPS system all should facilitate doctors to perform such clinical experiments.
Study Shows Patient’s Own Stem Cells Help Stroke Recovery: 16 Treated Patients Improve in Comparison to 36 Controls
Lee et al Stem Cells 28:1099
Stroke is caused by blocked circulation to parts of the brain usually as a result of a blood clot. Outcomes of stroke are generally proportional to the length of time the circulation was blocked and to the amount of brain tissue injury and death. Although the introduction of “clot busters” has improved outcomes in these patients, substantially morbidity and mortality still occurs. Numerous pharmaceutical approaches have been attempted in the treatment of stroke, both from the perspective of inhibiting tissue damage, and more recently trying to stimulate regeneration of injured brain tissue. To date clinical progress in this area has been relatively insignificant. In fact, in the pharmaceutical industry the condition of stroke has been referred to as a “graveyard for biotechs”.
One potentially promising treatment for stroke would be to augment the body’s own repair processes through activation of stem cells that are either pre-existing in the body, or through administration of stem cells either directly into the damaged brain tissue or areas associated with the damaged brain tissue. Rationale for this includes observations that stem cells from the bone marrow called endothelial progenitor cells are known to enter circulation in patients with stroke. A study from Dunac et al in France demonstrated that patients who have a higher degree of stem cells in circulation after a stroke have a better neurological outcome in comparison to patients who have lower numbers of circulating stem cells. In rats which are given a stroke experimental by ligation of one of the arteries that feeds the brain, called the middle cerebral artery, administration of human or rat stem cells reduces the size of brain damage, as well as causes regeneration of new neurons. Additionally, animal studies have demonstrated that administration of stem cells causes improved behavior as compared to animals receiving control cells or saline.
One reason why there exists a belief in the field that bone marrow derived cells may be capable of generating new neurons is that in female recipients of bone marrow transplant nerve cells have been found that express the Y-chromosome (Weimann et al. Contribution of transplanted bone marrow cells to purkinje neurons in human adult brains Proc Natl Acad Sci USA 100:2088).
In a recent paper (Lee et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28:1099) a group from Korea reported what to date is the largest clinical trial of stem cells in stroke. The investigators used mesenchymal stem cells generated from the bone marrow of the stroke patients. These cells are believed to be capable of generating new neurons, as well as producing growth factors that stimulate the brain to heal itself. Mesenchymal stem cells are currently used in clinical trials in the US and internationally for treatment of graft versus host disease, heart failure, and critical limb ischemia (an advanced form of peripheral artery disease that causes 100-200,000 amputations per year). Advantages of mesenchymal stem cells include: a) ability to be expanded in tissue culture; b) Well-known safety profile; and c) Ability to use between individuals without need for matching.
In the study discussed, the investigators selected 52 patients with a defined type of stroke (non-lacunar infarction within the middle cerebral artery territory). Patients were selected 7 days after the stroke in order to have a standardized level of dysfunction. It was previously published that before 7 days the patient may have a sudden increase or decrease in neurological function, but after 7 days post-stroke the neurological function remains stable.
The investigators extracted 5 ml of bone marrow from 16 patients and expanded the mesenchymal stem cells over a 4 week period. The mesenchymal stem cells were defined as cells expressing the markers CD105 (SH-2) and SH-4. Cells were grown as adherent cells in media containing fetal calf serum. The 16 patients received two administrations of 50 million cells intravenously spread apart by a week.
Patients were followed for an average of 117 weeks, with some patients followed as long as 5-years after the stroke. There was a statistically significant difference in overall survival in the patients that received the mesenchymal stem cells as compared to controls. Specifically, 4 of the 16 patients who received the mesenchymal stem cells passed away during the follow-up period as compared to 21 of the 36 control patients.
In studies of embryonic or fetal stem cells, one of the major concerns is development of tumors. This stems from the fact that administration of embryonic stem cells into immune deficient animals causes tumors called teratomas, and in humans there is at least one documented case of a brain tumor developing in a patient who received fetal derived stem cells. Of the patients administered mesenchymal stem cells, no tumors were detected. This is important because this study has one of the longest follow up periods.
Functional improvements as quantified by the modified Rankin Score were noted in patients receiving stem cells, whereas controls overall suffered a decline in function. Specifically, function was assessed at a median of 3.5 years in the control group and 3.2 years in the mesenchymal stem cell treated group. Function was assessed by doctors where were “blinded” to which patient received stem cells and which patient was in the control group. In the control group 13 of 26 patients had a negative rank, which indicates an improved functional outcome for each patient, whereas 21 patients had a positive rank, which means worse outcome. In contrast, in the treatment group 11 of the 16 patients had a negative rank. The difference between groups reached statistical significance.
In 9 patients of the group that received stem cells, a correlation was studied between the cytokine SDF-1 and functional outcome. Functional outcome was determined both by the modified Rankin score as well as by the Barthel index. A positive correlation was found between levels of SDF-1 at the time of MSC treatment and functional outcome in the patients studied. This protein is known to be involved in recruiting stem cells to the site of injury. Given that in this study the stem cells were administered intravenously and not locally (eg by sterotactic injection), it would be logical that a correlation exist between chemotactic signaling and improved outcome. Currently there are companies such as Juvantis, that are administering plasmids expressing SDF-1 in order to induce homing of endogenous stem cells into cardiac infarcts. It is interesting that the same priniciple may be valid in situations of ischemic stroke. To date no studies have been performed clinically using co-administration of stem cells and SDF-1, however, myoblasts transfected with SDF-1 have been used in a clinical trial in Jordan by the company BioHeart for treatment of heart failure.
One other interesting finding of the study besides lack of ectopic tissue or tumor formation is that no adverse effects were associated with using stem cells grown in fetal calf serum. There has been concern in the literature, particularly the academic literature, that fetal calf serum may induce autoimmunity or sensitization upon second MSC administration. This did not appear to be the case.
