Gene Therapy Increases Stem Cell Recruitment to Heart and Improves Heart Function


Data from a Phase 2 clinical trial is creating quite a stir in cardiology circles. According to the findings of this study, the single administration of a gene on a non-viral-derived plasmid improves cardiac structure, function, serum biomarkers and clinical status in patients with severe ischemic heart failure one year after treatment.

The results from the final 12-months of the Phase 2 STOP-HF clinical trial for the JVS-100 treatment were presented at the European Society of Cardiology – Heart Failure 2015 meeting by the developer of this technology: Juventas Therapeutics Inc. The founder of Juventas, Marc Penn, M.D., Ph.D., FACC, is also the medical officer and director of Cardiovascular Research and Cardiovascular Medicine Fellowship at Summa Health in Akron, Ohio. Dr. Penn presented the results of this randomized, double-blind, placebo-controlled STOP-HF trial, which included treatments on 93 patients at 16 different clinical centers in the United States.

“The results from STOP-HF demonstrate that a single administration of 30 mg of JVS-100 has the potential to improve cardiac function, structure, serum biomarkers and clinical status in a population with advanced chronic heart failure who are symptomatic and present with poor cardiac function,” stated Dr. Penn. “These findings combined with our deep understanding of SDF-1 biology will guide future clinical trials in which we plan to prospectively study the patient population that demonstrated the most pronounced response to JVS-100. In addition, we will further our understanding of JVS-100 by determining if a second administration of drug may enhance benefits beyond those we observed with a single administration.”

These study. some patients received a 30 mg dose of JVS-100 while others received a placebo.  Patients who received JVS-100 showed definite improvements 12 months after treatment.  The cardiac function and heart structure of the patients who received JVS-100 were far better than those who had received the placebo.  JVS-100-treated patients showed a changed in left ventricle ejection fraction of 3.5% relative to placebo, and left ventricular end-systolic volume of 8.5 ml over placebo.  When patients were asked to walk for six minutes, the JVS-100-treated patients were better than patients who had received the placebo.  Likewise, when patients were given the Minnesota Living with Heart Failure Questionnaire, the JVS-100-treat patients had a better score than those who had received the placebo.  Also, there were no unanticipated serious adverse events related to the drug reported for the study.

JVS-100 is a non-viral DNA plasmid gene therapy. Plasmids are small circles of DNA that are relatively easy to manipulate, grow and propagate in bacterial cells. In the case of the JV-100 treatment, the plasmid encodes a protein called stromal cell-derived factor 1 (SDF-1). SDF-1 is a naturally occurring signaling protein that recruits stem cells from bone marrow to the site of SDF-1 expression. SDF-1, therefore, acts as a stem cell recruitment factor that summons stem cells to the places where they are needed.

When JV-100 is delivered directly to a site of tissue injury, it induces the expression of SDF-1 protein into the local environment for a period of approximately three weeks. SDF-1 secretion creates a homing signal that recruits the body’s own stem cells to the site of injury to induce tissue repair and regeneration.

Juventas is developing JVS-100 into a treatment of advanced chronic cardiovascular disease, including heart failure and late stage peripheral artery disease.

These improvements in heart function are relatively modest.  Therefore, it is difficult to get too excited about these results.  Also, Alexey Bersenev, a umbilical cord stem cell researcher, noted that the primary end points (or goalposts) for this trial were not met, and that makes this an unsuccessful trial.  Despite this bad news, JV-100 does seem to be safe, and the theory seems sound, even if the results are more than a little underwhelming.

MSCs for Tissue Engineered Tracheas and Enhanced Fracture Healing


For all my readers who have ever broken a bone, this one’s for you.

Setting a broken bone properly can lead to the healing of a broken bone, but large fractures that generate gaps in bones are very hard to heal. Stem cell therapy in combination with small protein molecules called cytokines has the potential to improve bone repair, since cytokines summon resident stem cells to migrate and home to the injured site. Having said that, the engraftment, participation and recruitment of other cells within the regenerating tissue are equally important.

To stimulate stem cell-mediated healing, University College London scientists over-expressed the SDF-1 protein in mesenchymal stem cells. Since SDF-1 is a stem cell-recruitment protein, it seems reasonable to suspect that these engineered cells would effectively increase the migration of native cells to the site of fracture and enhance bone repair.

Once they made SDF-1-expressing mesenchymal stem cells, Chih-Yuan Ho and colleagues showed that these cells increased the migration of non-transfected cells in a cell culture system.

Once these SDF-1-expressing mesenchymal stem cells were implanted into rats with large bone defects, bone marrow mesenchymal stem cells that over-expressed SDF-1 showed significantly more new bone formation within the gap and less bone mineral loss at the areas next to the defect site during the early bone healing stage.

Thus, SDF-1 plays an important role in accelerating fracture repair and contributing to bone repair, at least in this rat model. SDF-1 does this by recruiting more host stem cells to the defect site and encouraging their differentiation into bone cells, which go on to produce good-quality bone.  This paper appeared the the journal Tissue Engineering, Part A.

In a second paper that appeared in the Annals of Biomedical Engineering, mesenchymal stem cells were used to tissue engineer tracheae. In this case a biocompatible scaffold was seeded various with various cells and this strategy could be a solution for tracheal reconstruction.

Yoo Seob Shin and colleagues seeded mesenchymal stem cells (MSCs) on a scaffold made from pig cartilage powder (PCP). The PCP was made with minced and decellularized pig joint cartilage and was molded into a 5 × 12 mm (height × diameter) scaffold. Mesenchymal stem cells from the bone marrow of young rabbits were grown in culture and then cultured with the PCP scaffold. After 7 weeks in culture, these tracheal implants were transplanted on a 5 × 10 mm tracheal defect in six rabbits, which were evaluated 6 and 10 weeks after the operation.

None of the six rabbits showed any sign of respiratory distress, and endoscopic examination of these tissue engineered tracheae showed that the a normal-looking respiratory epithelium completely covered the regenerated trachea. These trachea also displayed no signs of collapse or blockage.

The tissue engineered tracheae were also scanned and modeled on a computer model (luminal contour). The reconstructed areas of the trachea were the right width and dimensions compared to normal adjacent trachea and were not narrow.

Detailed microscopic tissue examinations of the tissue engineered tracheae showed that the new cartilage was successfully produced by the seeded mesenchymal stem cells and there was only a minimal degree of inflammation or granulation tissue that forms on the surfaces of wounds during the healing process. This shows that the implants did not trigger a massive inflammatory response that damaged resident or implanted tissue.

The outer surfaces of tracheal cells are decorated with tiny beating hairs called cilia that constantly beat to clear particles from the respiratory system. There are also cells that secrete mucus, which acts like fly paper for invading pollutants, particles or microorganisms. in the tissue engineered tracheae, ciliary beating frequency of the regenerated epithelium was not significantly different from the normal adjacent mucosa.

Thus, mesenchymal stem cells from bone marrow seeded on a PCP scaffold successfully restored not only the shape but also the function of the trachea without any signs of graft rejection.

Bones and trachea – mesenchymal stem cells pack a powerful healing punch!!

Stem Cell Homing Factor Used to Treat Heart Patients


In a clinical trial that is probably one of the first of its kind, researchers from the laboratory of Marc Penn at the Summa Cardiovascular Institute in Akron, Ohio, activated the stem cells of heart failure patients by means of gene therapy.

Penn and his colleagues delivered a gene that encodes stromal-cell derived factor-1 or SDF-1. SDF-1 is a member of the chemokine family of signaling proteins, and chemokines are proteins that direct cells to get up and move somewhere. Thus, for stem cells, SDF-1 acts as a kind of “homing” signal.

Stromal-cell derived factor
Stromal-cell derived factor

In this unique study, Penn and his collaborators introduced SDF-1 into the heart in order to summon stem cells to the site of injury and enhance the body’s stem cell-based repair process. In a typical stem cell-based study, researchers extract and expand the number of cells, then deliver them back to the subject, but in this study, no stem cells were extracted. Instead they were summoned to the site of injury by SDF-1.

Marc Penn, professor of medicine at Northeast Ohio Medical University in Rootstown, Ohio and the director of research at Summa Cardiovascular Institute said of his clinical trial: “We believe stem cells are always trying to repair tissue, but they don’t do it well — not because we lack stem cells but, rather, the signals that regulate our stem cells are impaired.”

Previous research by Penn and colleagues has shown SDF-1 activates and recruits the body’s stem cells to sites of injury and this increases healing. Under normal conditions, SDF-1 is made after an injury but its effects are short-lived. For example, SDF-1 is naturally expressed after a heart attack but this augmented expression of SDF-1 only lasts only a week.

In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients’ stem cells. The trial enrolled 17 NYHA Class III heart failure patients, with left ventricular ejection fractions less than 40% and an average time from heart attack of 7.3 years. Three escalating JVS-100 doses were evaluated: 5 mg (cohort 1), 15 mg (cohort 2) and 30 mg (cohort 3). The average age of the participants was 66 years old.

Researchers injected one of three doses of the SDF-1 gene (5mg, 15mg or 30mg) into the hearts of these patients, and monitored them for up to a year. Four months after treatment, they found:
1. Patients improved their average distance by 40 meters during a six-minute walking test.
2. Patients reported improved quality of life.
3. The heart’s pumping ability improved, particularly for those receiving the two highest doses of SDF-1 compared to the lowest dose.
4. No apparent side effects occurred with treatment.
According to Penn, “We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level,” Penn said. “They still had evidence of damage, but they functioned better and were feeling better.”

Penn’s study suggests that our stem cells have the potential to induce healing without having to be taken out of the body. Penn said, “Our study also shows gene therapy has the potential to help people heal their own hearts.”

At the start of the study, participants didn’t have significant reversible heart damage, but lacked blood flow in the areas bordering their damaged heart tissue. The study’s results — consistent with other animal and laboratory studies of SDF-1 — suggest that SDF-1 gene injections can increase blood flow around an area of damaged tissue, which has been deemed irreversible by other testing.

In further research, Penn and his team are comparing results from heart failure patients receiving SDF-1 with patients who are not receiving SDF-1. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years, Penn said.