Fat-Based Stem Cells in the PRECISE Trial Stabilizes Exercise Performance in Chronic Heart Disease Patients


Cytori Therapeutics has announced the publication of safety and efficacy data from a 36-month European clinical trial of Cytori Cell Therapy in patients with chronic ischemic heart failure. Final data from the Company’s PRECISE trial, a 27-patient, prospective, randomized, double-blind, placebo-controlled, feasibility trial (Phase I/IIA), demonstrated statistically significant differences in cardiac functional capacity between treated and placebo groups.

Their research will appear in the upcoming issue of the American Heart Journal. Cytori Cell Therapy is a mixed population of adipose derived regenerative cells (ADRCs™) extracted from a patient’s own adipose tissue using Cytori’s proprietary Celution® System.

“The PRECISE trial is the first-in-man trial involving the myocardial injection of ADRCs for heart disease,” said Dr. Emerson Perin , Co-Principal Investigator of the trial. “By demonstrating a strong safety profile and suggesting that the use of ADRCs may preserve functional capacity, the data indicates that this therapy may have meaningful impacts on the lives of these very sick patients.”

This particular publication was co-authored by trial investigators Drs. Emerson C. Perin at Texas Heart Institute, Francisco Fernández-Avilés at Hospital Universitario Gregorio Marañón and others. This clinical trial shows that the procedure was safe, feasible and showed indications of a favorable benefit to the patients who received it. The study demonstrated that fat harvest through liposuction could be performed safely in cardiac patients. Exercise capacity as reflected by maximum oxygen consumption (MVO2) during treadmill testing, a reflection of cardiac functional capacity, was sustained in the ADRC treated group but declined in the placebo group at 6 and 18 months. Statistically significant differences were observed between the two groups.

“These results supported the design of the ongoing U.S. Phase II ATHENA trial that is evaluating a similar patient population,” said Steven Kesten , M.D., Chief Medical Officer for Cytori. “We are encouraged by the sustained effects in functional endpoints, particularly MVO2, which is a relevant clinical endpoint in heart disease, and is an aid in directing treatment options, such as assist devices or heart transplant. We look forward to reporting the initial six-month results from the ATHENA trial.”

Additionally, other data trends in this study suggest that ADRC therapy may have a modest beneficial effect in stabilization of the heart scar tissue. To understand the meaning of this benefit, remember that ischemic heart disease might also be known as coronary artery disease (CAD), atherosclerotic heart disease, or coronary heart disease. Ischemic Heart Disease is the most common type of heart disease and cause of heart attacks. This disease is typically caused by plaque build up along the inner walls of the arteries of the heart, which leads to narrowing of the arteries and reduction of blood flow to the heart. After a heart attack, the region of the heart that was deprived of oxygen for a period time dies and the dead heart muscle tissue is replaced by scar tissue that contracts over time, but does not contract or conduct heartbeat impulses. In this study, the scar mass of the left ventricle remained consistent in ADRC-treated patients at six months compared to an increase in control patients. This suggests that ADRCs may prevent scar tissue from increasing. Other endpoints such as ventricular volumes and ejection fraction showed inconsistent findings.

In the PRECISE trial, all patients were treated with standard-of-care and subsequently underwent a liposuction procedure. Each patient’s adipose tissue was processed using Cytori’s proprietary Celution® System to prepare the cell therapy. Cells (n=21) or placebo (n=6) were injected into areas of the heart muscle that were severely damaged but still viable and reversible using the NOGA XP System.

Cytori is currently enrolling patients in the U.S. ATHENA and ATHENA II trials, both 45 patient prospective, randomized, double-blind, placebo-controlled trials investigating a lower and a higher dose, respectively, of Cytori Cell Therapy in a similar patient population as PRECISE.

The PRECISE study is a small study, but the fact that it was double-blinded and placebo controlled makes it an important study. The experimental group showed a clear stabilization of maximum oxygen consumption as opposed to the control group, whose exercise tolerance decreased during the course of the trial. This is potentially significant.  The ADRCs could be preventing the heart from enlarging as a result of working harder.

Questions, however, remain.  For example, is this a short-term effect or does it maintain its effect over the long-term period? To answer that, patient follow-up is necessary. Second, the other physiological parameters showed confusing outcomes (ejection fraction, end-diastolic volume, and so on).  If the ADRCs are truly helping the heart function better, then why don’t the physiological parameters used to measure heart function show some semblance of improvement?  The stabilization of the maximum oxygen consumption stabilization might not mean much in retrospect if it is short-term.

A larger trial like the ATHENA study will be more powerful. Hopefully these PRECISE patients will be followed and examined several years after the treatment to determine the duration of the ADR-provided benefits.

Repairing Muscles in Muscular Dystrophy Depends on the Degree of Muscle Deterioration


Pier Lorenzo Puri, M.D., an associate professor at Sanford-Burnham Medical Research Institute (Sanford-Burnham), has led a research team that work in collaboration with Fondazione Santa Lucia in Rome, Italy, to characterize the mechanism by which a class of drugs called “HDACis” drive muscle-cell regeneration in the early stages of dystrophic muscles, but fail to work in late stages. These findings are integral for designing HDACis drugs for Duchenne muscular dystrophy (DMD), which presently, is an incurable muscle-wasting disease.

Puri’s research was published April 15th, 2014 edition of the journal Genes and Development. In their paper, Puri and his colleagues used mouse models of DMD to show how special cells known as “fibro-adipogenic progenitor cells” or FAPs, direct muscle regeneration. FAPs reside in the spaces between muscle fibers and detect those cues that indicate that muscles have been damaged. In response to muscle damage, FAPs direct muscle stem cells, known as satellite cells, to rebuild muscle.

 HDAC inhibitors (HDACi) promote muscle regeneration in a mouse model of Duchenne Muscular Dystrophy at early stages of disease by targeting fibro-adipogenic progenitors (FAPs). Staining of FAPs from muscles of HDACi-treated young mdx mice reveals presence of differentiated muscle cells (green) at the expense of fat cells (red). Nuclei are stained in blue. Image: Lorenzo Puri, M.D.

HDAC inhibitors (HDACi) promote muscle regeneration in a mouse model of Duchenne Muscular Dystrophy at early stages of disease by targeting fibro-adipogenic progenitors (FAPs). Staining of FAPs from muscles of HDACi-treated young mdx mice reveals presence of differentiated muscle cells (green) at the expense of fat cells (red). Nuclei are stained in blue. Image: Lorenzo Puri, M.D.

“HDACis create an environment conducive for FAPs to direct muscle regeneration—but only during the early stages of DMD progression in mice,” said Puri. “At some point, DMD progresses to a pathological point of no return and become permanently resistant to muscle-regeneration cures and to HDACis.”

Indeed, Puri’s research showed exactly that; namely that FAPs embedded in muscle that was in the earlier stages of muscular dystrophy responded robustly to HDACis and upregulated a wide range of muscle-specific genes. In contrast, FAPs from late-stage dystrophic muscles were resistant to HDACi-induced muscle-specific gene expression and failed to activate satellite cells.

HDACis stands for histone deacetylase inhibitors. These are epigenetic drugs that regulate the accessibility of those genes that code for muscle proteins. HDACis ensure that the DNA within cells is open and easily accessible to the gene expression machinery. In the presence of FAPs, in particular, rev up their support for muscle regeneration. Under conditions of normal wear and tear, FAPs direct stem cells within the muscle to regenerate and repair damaged muscle. However in patients with DMD, the persistent breakdown of muscle cells creates a chaotic environment that overwhelms the ability of the FAP’s to direct muscle regeneration.

Puri collaborated with Italian colleagues at Fondazione Santa Lucia, Italfarmaco, and Parent Project Muscular Dystrophy, an advocacy association. The goal of this research is to develop HDACis for the treatment of DMD. To that end, Puri and others have launched a clinical trial with DMD boys.

“Our study is important because it provides the rationale for the clinical development of HDACis to treat DMD,” said Puri. “And, now that we understand the mechanics and sensitivities of the muscle-regeneration system, we have the rationale and can use new tools to select patients most likely to benefit from HDACIs based on their FAP profile, predict outcomes, and see how long patients should remain on the therapy.”

“Duchenne muscular dystrophy patients and their families rely on important research such as that performed by Dr. Puri,” said Debra Miller, Founder of Cure Duchenne, a patient advocacy group. “Our efforts at Cure Duchenne are to support leading scientists in the world to bring life-saving drugs to help this generation of Duchenne boys, and our vision is to cure Duchenne muscular dystrophy. Every added piece of knowledge about the disease brings us closer to realizing our goals.”

The Puri paper also shows why trying to regenerate muscle cells in severely affected individuals is not feasible, since the dystrophic muscles have deteriorated to the point of no return. This will definitely influence the construction of treatment strategies for patients with muscular dystrophy.