Stem Cell Treatments to Improve Blood Flow in Angina Patients


Angina pectoris is defined as chest pain or discomfort that results from poor blood flow through the blood vessels in the heart and is usually activated by activity or stress.

In Los Angeles, California, physicians have initiated a double-blind, multicenter Phase III clinical trial that uses a patient’s own blood-derived stem cells to restore circulation to the heart of angina patients.

This procedure utilizes state-of-the-art imaging technology to map the heart and generate a three-dimensional image of the heart. These sophisticated images will guide the physicians as they inject stem cells into targeted sites in the heart.

This is a double-blinded study, which means that neither the patients nor the researcher will know who is receiving stem-cell injections and who is receiving the placebo.

The institution at which this study is being conducted, University of Los Angeles (UCLA), is attempting to establish evidence for a stem cell treatment that might be approved by the US Food and Drug Administration for patients with refractory angina. The subjects in this study had received the standard types of care but did not receive relief. Therefore by enrolling in this trial, these patients had nothing to lose.

Dr. Ali Nasir, assistant professor of cardiology at the David Geffen School of Medicine and co-principal investigator of this study, said: “We’re hoping to offer patients who have no other options a treatment that will alleviate their severe chest pain and improve their quality of life.”

Before injecting the stem cells or the placebo, the team examined the three-dimensional image of the heart and ascertained the health of the heart muscle and voltage it generated. Damaged areas of the heart fail to produce adequate quantities of voltage and show low levels of energy.

Jonathan Tobis, clinical professor of cardiology and director of interventional cardiology research at Geffen School of Medicine, said: “We are able to tell by the voltage levels and motion which area of the [heart] muscle is scarred or abnormal and not getting enough blood and oxygen. We then targeted the injections to the areas just adjacent to the scarred and abnormal heart muscle to try to restore some of the blood flow.”

What did they inject? The UCLA team extracted bone marrow from the pelvic bones and isolated CD34+ cells. CD34 refers to a cell surface protein that is found on bone marrow stem cells and mediates the adhesion of bone marrow stem cells to the bone marrow matrix. It is found on the surfaces of hematopoietic stem cells, placental cells, a subset of mesenchymal stem cells, endothelial progenitor cells, and endothelial cells of blood vessels. These are not the only cells that express this cell surface protein, but it does list the important cells for our purposes. Once the CD34+ cells were isolated, the were injected into the heart through a catheter that was inserted into a vein in the groin.

CD34

The team hopes that these cells (a mixture of mesenchymal stem cells, hematopoietic stem cells, and endothelial progenitor cells) will stimulate the growth of new blood vessels (angiogenesis) in the heart, and improve blood flow and oxygen delivery to the heart muscle.

“We will be tracking patients to see how they’re doing,” said William Suh MD, assistant clinical professor of medicine in the division of cardiology at Geffen School of Medicine.

The goal of this study is to enroll 444 patients nation-wide, of which 222 will receive the stem cell treatment, 111 will receive the placebo, and 111 who will be given standard heart care.

Major Clinical Trial Finds Bone Marrow Stem Cell Treatments Provide No Benefits After a Heart Attack


A large and very well designed and carefully controlled clinical trial known as TIME has failed to demonstrate any benefit for infusions of bone marrow stem cells into the heart 3-7 days after a heart attack.  This study comes on the heals of a similar clinical study known as LateTIME, which stands for Late Timing In Myocardial infarction Evaluation, and tested the effects of bone marrow stem cells infusions into the heart of heat attack patients 2-3 weeks after a heart attack.

LateTIME enrolled 87 heart attack patients, and harvested their bone marrow stem cells.  The stem cells were delivered into the hearts through the coronary arteries, but some received a placebo.  All patients had their ejection fractions measured, their heart wall motions in the damaged areas of the heart and outside the damaged areas and the size of their infarcts.  There were no significant changes in any of these characteristics after six months. Because another large clinical study known as the REPAIR-AMI study showed significant differences between heart attack patients that had received the placebo and those that had received bone marrow stem cells 3-7 days after a heart attack, this research group, known as the Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Institutes of Health, decided the test their bone marrow infusions at this same time frame.

TIME was similar in design to LateTIME.  This study enrolled 120 patients that had suffered a heart attack and all patients received either an infusion of 150 million bone marrow stem cells or a placebo within 12 hours of bone marrow aspiration and cell processing either 3 days after the heart attack to 7 days.  The researchers examined the changes in ejection fraction, movement of the heart wall, and the number of major adverse cardiovascular events plus the changes in the infarct size.

The results were resoundingly negative.  At 6 months after stem cell infusion, there was no significant increase in ejection fractions versus the placebo and no significant treatment effect on the function of the left ventricle in either the infarct or the border zones.  These findings were the same for those patients that received bone marrow stem cell infusions 3 days after their heart attack or 7 days after their heart attacks.  Fortunately, the incidence of major adverse events were rare among all treatment groups.

Despite the negative results for these clinical trials, there are a few silver linings.  First of all, the highly controlled nature of this trial sets a standard for all clinical trials to come.  A constant number of stem cells were delivered in every patient, and because the stem cells were delivered soon after they were harvested, there were no potential issues about bone marrow storage.

Jay Traverse, the lead author of this study, made this point about this trial:  “With this baseline now set, we can start to adjust some of the components of the protocol to grow and administer stem cell [sic] to find cases where the procedure may improve function.  For example, this therapy may work better in different population groups, or we might need to use new cell types or new methods of delivery.”

When one examines the data for this study, it is clear that some patients definitely improved dramatically, whereas others did not.  Below is a figure from the Traverse et al paper that shows individual patient’s heart function data 6 months after the stem cell infusions.

BMC indicates bone marrow mononuclear cell; MI, myocardial infarction.

From examining these data even cursorily, it is clear that some patients improved dramatically while others tanked.  Traverse is convinced that bone marrow stem cell infusions help some people, but not others (just like any other treatment).  He is convinced that by mining these data, he can begin to understand who these patients are who are helped by bone marrow stem cell transplants and who are not.  Also, the stem cells of these patients have been stored.  Hopefully, further work with them will help Traverse and his colleagues clarify what, if anything, about the bone marrow of these patients makes them more likely to help their patients and so on.

There are some possible explanations for these negative results.  Whereas the positive REPAIR-AMI used the rather labor-intensive Ficoll gradient protocols for isolating mononculear cells from bone marrow aspirates, the TIME trials used and automated system for collecting the bone marrow mononuclear cells.  Cells isolated by the automated system have neither been tested in an animal model of heart attacks, nor established as efficacious in a human study of heart disease.  Therefore, it is possible that the bone marrow used in this study was largely dead.  Secondly, the cell products were kept in a solution that had a heparin concentration that is known to inhibit the migratory properties of mononuclear cells (See Seeger et al., Circ Res 2012 111(7): 1385-94).  Therefore, there is a possibility that the bone marrow used in this study was no good.  Until the bone marrow stem cells collected by this method are confirmed to be efficacious, judgment must be suspended.

Mesenchymal Stem Cells Can Potentially Treat Non-Union Fractures


Sometimes bone fractures have trouble healing. Such fractures are called “stable non-union fractures,” and they represent major clinical challenges. There are few treatment options for stable non-union fractures, and such conditions represent a major health issue. Fracture treatment options include bone grafting and/or remodeling of the fracture through open reduction and internal fixation (ORIF). In general, ORIF involves the use of plates, screws or even an intramedullary rod to stabilize the bone. Other, less-invasive care options such as treatment with bone morphogenic proteins (BMPs) and other types of bone stimulators are also available.

Can mesenchymal stem cells help such fractures heal better? Centeno and his colleagues at Regenexx conducted their own original research study that shows that some patients probably can be helped by the same sorts of procedures that they use to treat knees. This procedure includes bone marrow aspiration from the crest of the top of the pelvis (the ilium). The mesenchymal stem cells are isolated from the bone marrow and cultured for a few days. Then the expanded and prepared mesenchymal stem cells are applied precisely to the area that needs healing by means of c-Arm fluoroscopy. Sounds good? Yes it does, but to show that it works requires a tried and true clinical study. Centeno’s group has done exactly that, but the number of patients in this study is small. Still this paper represents one of the first examinations of stem cells treatments for stubborn fractures they resist healing.

In this paper, six patients were evaluated. All six had chronic fractures that had not healed (chronic fracture non-unions). There were four women and two men in this experimental group, and they had suffered from these fractures for an average of 8.75 months. The range of the times the patients had lived with these fractures ranged from 4- 18 months, but one patient had lived with their fracture for over 100 months.

All six patient were treated with their own stem cells that were extracted by means of bone marrow aspirations, cultured in the laboratory for 3- 7 passages, and then suspended in phosphate-buffered saline and lysate from peripheral blood platelets. All mesenchymal stem cells were assessed by microscopic examination and flow cytometry to ensure that they expressed the proper surface proteins. Mesenchymal stem cells were then injected percutaneously by means of a sterile trocar, guided by fluoroscopic imaging into the site of the stubborn fracture. To determine if the fractures healed, patients were scanned with X-rays, and computerized tomographic (CT) imaging.

Only five of the patients could be contacted for follow up, but the results are somewhat encouraging. The first patient was a 37-year old smoker (1/4 pack a day) who had suffered with a non-healing fracture for 9 months, but only 2 months after the treatment, was back to “full activities.” An X-ray at 14 months after healing showed excellent healing of the fracture.

The second patient was an 82-year old woman who had suffered from several fractures because of osteoporosis. She had stem cells implanted into her fractured back, and by eight months after the treatment regime, she showed advanced healing of her back fracture. Within four to six weeks after the transplant, the patient walked normally for her age and enjoyed new activities, albeit with age restrictions.

The third patient was a 68-year old woman with a long-time history of multiple sclerosis. She had an 18-month fracture that had not healed in her foot and had to walk with a walking boot immobilizer. Follow-up X-rays showed that after 2 and 6 months she had moderate healing of her fracture and returned to normal activities by 4-6 weeks after the transplant. Unfortunately, she dropped an object on the same foot at 7 months after the procedure and no further follow-up seemed practical.

The fourth patient is a 59 year old woman who had a 40-year history of a traumatic hip fracture and hamstring tear. Unfortunately, her follow up x-rays failed to show any signs of healing.

The fifth patient is a 67-year old man with a 4-month lower leg fracture. He also had type II diabetes mellitus, and coronary artery disease. This patient returned to full walking 4-6 weeks after the procedure. 5 months after the transplant, his x-rays showed signs of healing. No further follow up was possible.

Four of the six patients treated with their own mesenchymal stem cells showed good healing of the fractures that resisted healing through conventional means. The only fracture that showed no signs of healing was a 40-year old fracture that was difficult to immobilize. It is possible that the lack of immobilization caused the bone, which reacts to stress forces, caused this fracture that had adapted to being broken, and could no longer produce signals necessary for repair.

While this study is preliminary, the results support the hypothesis that a patient’s own mesenchymal stem cells are a potential alternative treatment for the treatment of stubborn, fractures that refuse to heal.

Severe Shoulder Rotator Cuff Tear treated with Stem Cells


Shoulder rotator-cuff tears are painful and usually require surgery. Can stem cells treat such a condition? Regenexx has attempted to do just that with surprising success.

One patient who is called JS had a particularly bad rotator cuff tear that included a retraction of the rotator cuff muscle. Stem cell treatments might not help heal this tear since the two ends of the tendon or muscle need to be surgically pulled together for the stem cells to heal the tendon. When the tendon experiences a retracted tear of the rotator cuff muscle the two sides of the tear pull back like a rubber band. The tendon bunches up on either side of the tear, and it is difficult to envision how stem cells might heal such a tear, since tears where the two ends of the tear are close together can be filled in with stem cells that are precisely applied to the tear.

All of this changed, however, with the treatment of a patient known as JS. He had a 1.5 cm retracted tear from a weight-lifting injury. After reluctantly agreeing to treat him with a mesenchymal stem cell application, they placed the shoulder in a splint to bring the two ends of the tear closer together. Then JS received a Regenexx-SD procedure that was followed up with a Regenexx-SCP procedure. The Regenexx-SD procedure takes mesenchymal and hematopoietic stem cells from a bone marrow aspiration and then mixes them with a preparation of platelets taken from peripheral blood. Regenexx-SCP treatment uses a specific stem cell population from bone marrow (CD66e+ cells) that are mixed with a platelet-rich mixture from blood serum and injected into joints.

The Regenexx physicians had low expectations of this procedure, but to their surprise, JS reported a 99% improvement over the three months. A follow-up ultrasound demonstrated excellent healing with some fill-in of the retracted gap.  For MRIs for this patient’s shoulder before and after the treatment, see here.

One year after the shoulder stem cell injections, the improvement due to precision injections of the patient’s own stem cells is nothing short of amazing. The large gap in the rotator cuff  is now healed.  For MRI images of JS’s shoulder one year after the Regenexx treatment, see here.  JS did require a specialized treatment and bracing protocol unique to the Regenexx procedures and developed by Dr. Hanson. This is an example of stem-based orthopedic surgery at its best.

BrainStorm Announces that There Are No Dangerous Side Effects Observed in NurOwn Trial


A developer of innovative stem cell technologies, BrainStorm Cell Therapeutics Inc. has developed a stem cell treatment called NurOwn for central nervous system-based disorders. NurOwn™ is a product derived from human bone marrow mesenchymal stem cells. After these cells are collected from a patient by means of a bone marrow aspiration (which not nearly as invasive as a bone marrow biopsy), they are differentiated into nerve-like cells that can release the neurotransmitter dopamine and a nervous system-specific growth factor called glial-derived neurotrophic factor (GDNF). Dopamine cell damage and death is the hallmark of Parkinson’s Disease (PD), and GDNF-producing cells can protect healthy dopamine-producing cells and repair degenerated cells. This halts the progression of PD and other neurodegenerative diseases. BrainStorm’s NurOwn™ therapy for PD replaces degenerated dopamine-producing nerve cells and strengthens them with GDNF.

BrainStorm has just announced patient data from its ALS combined phase I & II human clinical trial. ALS patients who were treated with NurOwn, a stem cell-based product that BrainStorm had developed, did not show any significant side effects to the NurOwn treatment. Therefore, so far, NurOwn seems to be safe.

The leader of this clinical trial at Hadassah Medical Center, Prof. Dimitrios Karussis, stated, “There have been no significant side effects in the initial patients we have treated with BrainStorm’s NurOwn technology. In addition, even though we are conducting a safety trial, the early clinical follow-up of the patients treated with the stem cells shows indications of beneficial clinical effects, such as an improvement in breathing and swallowing ability as well as in muscular power. I am very excited about the safety results, as well as these indications of efficacy, we are seeing. This may represent the biggest hope in this field of degenerative diseases, like ALS.”

The Hadassah Medical Center ethics committee reviewed the safety data from the first four patients who were implanted with NurOwnTM, and concluded that the clinical trial should proceed with implanting the next group of ALS patients.

BrainStorm’s President, Chaim Lebovits, remarked: “We are happy to report that the first patients treated with our NurOwn technology did not present any significant side effects. This supports and strengthens our belief and trust in our technology. Based on the interim safety report, the hospital ethical and safety committee granted the company approval to proceed with treating the next patients. We are pleased with the progress we are making and look forward to continuing to demonstrate the safety of NurOwn in the future.”

This study is headed by Prof. Karussis, MD, PhD, head of Hadassah’s Multiple Sclerosis Center and a member of the International Steering Committees for Bone Marrow and Mesenchymal Stem Cells Transplantation in Multiple Sclerosis (MS), and a scientific team from BrainStorm headed by Prof. Eldad Melamed. This clinical trial is being conducted at Hadassah Medical Center in Israel in collaboration with BrainStorm and utilizes BrainStorm’s NurOwn technology for growing and modifying autologous adult human stem cells to treat ALS, which is often referred to as Lou Gehrig’s Disease. The initial phase of the study is designed to establish the safety of NurOwn, but will also be expanded later to assess efficacy of the treatment.