Mesoblast MPCs Improve Heart Function in Patients with Congestive Heart Failure


Mesoblast Limited is a biotechology company with a singular interest in developing cell-based, regenerative therapies to treat some rather common, but severe ailments. Mesoblast has a proprietary cell system based on specialized cells known as mesenchymal lineage adult stem cells. These mesenchymal lineage adult stem cells (MLASCs) are being designed to serve as ‘off-the-shelf’ cell products for treating heart conditions, orthopedic disorders, immunologic/inflammatory disorders and cancer.

Mesoblast has recently released the results of a Phase 2 clinical trial that utilized their therapeutic product MPC-150-IM and tested it in patients with chronic congestive heart failure. The results of this study were published in the journal Circulation Research, a high-impact journal of the American Heart Association.

Patients who suffer from advanced heart failure have a poor long-term prognosis and they also have few therapeutic options. The pumping power of their hearts is weaker than normal, and the blood moves through the heart and body at a slower than normal rate. Consequently, fluid pressure in the heart increases and the chambers of the heart respond by stretching to hold more blood to pump through the body or by thickening and becoming stiff. This helps to keep the blood moving, but the heart muscle walls may eventually weaken and become unable to pump as efficiently. The kidneys respond by causing the body to retain fluid (water) and salt, and if the fluid builds up in the arms, legs, ankles, feet, lungs, or other organs, the body becomes congested, and congestive heart failure is the term used to describe the condition.

Mesoblast decided to test their proprietary Mesenchymal Precursor Cells (MPCs) to potentially induce heart muscle repair, stimulate new blood vessel growth, decrease cell death and reduce scar formation. Earlier studies established that MPCs are safe to give to heart patients. This new study examined the ability of these cells to improve heart function in patients with congestive heart failure.

In this study, 60-patients were subjected to a blinded, placebo-controlled trial. MPCs were injected directly into the heart muscle. One of the Primary Endpoints of this study was safety.

Patients included those with ischemic or non-ischemic heart failure (due to left ventricular systolic dysfunction), and in both groups, MPC injections were feasible and safe. There was a similar incidence of adverse events across all control and treatment groups. The patients who were treated with MPCs did not show any clinically significant immune response again the injected MPCs.

When it came to the main Secondary Efficacy Endpoints, patients who were treated with the highest MPC dose showed the greatest improvement in left ventricular remodeling compared to controls as evidenced by significant reductions in Left Ventricular End Systolic Volume (LVESV; p=0.015), and Left Ventricular End Diastolic Volume (LVEDV; p=0.02), 6 months after the treatment. LVESV and LVEDV increase as the heart gets weaker, but in these patients, the LVESV and LVEDV decreased. There were also parallel improvements in ejection fraction, but these improvements were not statistically significant. Patients treated with the highest dose of MPCs also showed the greatest improvement in functional exercise capacity compared to controls (p=0.062) 12 months after receiving their treatments.

Finally, in a post-hoc analysis of all patients 36 months after treatment, patients treated with MPCs showed significantly lower incidence of major adverse cardiac events when compared to the control group (0% vs 33% HF-MACE by Kaplan-Meier, p=0.026 by log-rank).

In their article, entitled ‘A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Non-Ischemic Heart Failure’, the authors concluded that high-dose MPC treatment seems to reduce heart failure-related major adverse cardiovascular events and provide beneficial effects on adverse left ventricular remodeling.

Lead author and investigator Dr Emerson C. Perin, Director, Research in Cardiovascular Medicine and Medical Director of the Stem Cell Center at the Texas Heart Institute, said: “The findings from this trial are very encouraging and suggest that a high-dose of Mesoblast’s allogeneic cell-based therapy may decrease major clinical events associated with progressive heart failure for at least three years, including repeated hospitalizations or death.

“These effects appear to be due to the ability of these cells to positively impact on adverse cardiac remodeling associated with chronic heart failure. If these results are confirmed in the ongoing Phase 3 trial currently recruiting at our institution and elsewhere, this new therapy has the potential to change the paradigm for the management of patients with advanced heart failure and a high risk of hospitalization and death,” Dr Perin added.

A randomized, placebo-controlled Phase 3 trial using Mesoblast’s high-dose MPC 150M is being conducted by Mesoblast’s development and its commercial partner, Teva Pharmaceutical Industries Ltd. Presently, this study is actively enrolling patients across multiple clinical sites in North America.

Taiwanese Group Identifies Stem Cell-Based Drug to Rejuvenate Aged Hearts


A southern Taiwan-based National Cheng Kung University research team led by Patrick Ching-Ho Hsieh has discovered that a molecule called prostaglandin E2 can regenerate aged hearts in rodents.

This discovery provides a useful new perspective on heart regeneration and presents an effective option for heart disease patients other than heart transplant.

According to Hsieh, congestive heart disease and other cardiovascular diseases are a leading cause of morbidity and mortality throughout the world. There are some six million patients with congestive heart failure in the US alone and some 400,000 in Taiwan. Despite intensive drug, surgical and other medical interventions, 80 percent of all heart patients die within 8 years of diagnosis.

Even though several experiments and clinical trials have established that heart regeneration can take place, the means by which the heart regenerates is still not completely clear, and there are also no drugs to stimulate heart regeneration by the resident stem cell population in the heart.

Now, after seven years of hard work, Hsieh’s team has identified the critical time period and the essential player that directs heart repair.

Hsieh and his colleagues used genetically engineered mice that Hsieh had developed as a postdoctoral research fellow at Harvard Medical School. By using this transgenic mouse strain, Hsieh and others showed that the self-repair process of the heart begins 7 days after injury and peaks at 10 days after injury.

The “director” of this self-repair process is the molecule PGE2. PGE2 regulates heart-specific stem cell activities.

PGE2

“More importantly, both young and old mice have significant improvements for cardiac remodeling if you treat both of them [with] PGE2,” said Hsieh.

Hsieh’s team also established that PGE2 decreases expression of a gene associated with aging, TGF-beta1. PGE2 also rejuvenates the micro-environment of the aged cells, according to Hsieh.