By SHARON KINGMAN and TOM CLARK
CDU Contributing Editors

A team of French physicians said it has proof of principle that autologous cell therapy is a viable treatment for myocardial infarction. A post-mortem study carried out on one of 10 patients to receive the experimental treatment showed that the grafted cells survived in the heart, and that they started to make a type of muscle protein that is made by heart muscle.

This report gives further encouragement to the team, which already has embarked on a Phase II study of the treatment. The Phase II study is being run jointly by Genzyme Biosurgery, a subsidiary of Genzyme Corp. (Cambridge, Massachusetts), the biotechnology company Myosix SA (Paris) and the Assistance Publique Hopitaux de Paris (also Paris).

Albert Hagege, professor of cardiology at the Hospital Europeen Georges Pompidou (Paris), told CDU, "These results have allowed us for the first time to prove that the concept of putting skeletal muscle cells into heart muscle actually works in practice." Hagege, together with collaborators based at hospitals throughout Paris, reported the latest findings in a Feb. 8 research letter to The Lancet.

He said he was not surprised by the outcome of the study because many animal experiments carried out by the team had suggested that skeletal muscle cells could survive in the heart. But, he added, "many people over the years have told us that these cells could not survive in the fibrotic non-vascularized regions of the heart where we placed them, and these people are now surprised by these results" The therapy involves removing skeletal stem cells called myoblasts from one of the patient's own leg muscles, culturing the cells to increase their number and injecting them into the damaged myocardium following myocardial infarction.

As part of a Phase I trial carried out during 2000 and 2001, 10 patients underwent this procedure, while also undergoing coronary artery bypass grafting (CABG). One patient died almost immediately. The results reported in The Lancet relate to a patient belonging to this original group, who survived following the procedure for almost 18 months before dying from a stroke. Tests carried out on the heart muscle of that 72-year-old man showed that the region that had been injected with the myoblasts contained islets of adult skeletal muscle cells (myotubes) embedded in fibrotic heart muscle. There was no associated inflammation and no growth of new blood vessels. These muscle cells looked histologically normal for skeletal muscle, and experiments showed that they had cell marker proteins normally found on skeletal muscle, and that cell marker proteins that are normally found on cardiac muscle were absent.

Hagege said, "All muscle cells produce the protein myosin, but there are two isoforms of myosin," Hagege said. One is the fast form, found predominantly in skeletal muscle, and the slow form, found predominantly in cardiac muscle, which, he said, "is the form of the protein that is best for the type of work the heart muscle does. When we looked at the grafted cells, we found that they expressed a lot of the slow isoform of myosin."

Analysis showed that 35% of the grafted myotubes expressed only the fast isoform of myosin, 32% only the slow isoform and 33% expressed both isoforms. By contrast, analysis of a biopsy of the skeletal muscle from which the graft was taken had earlier shown that 55% of the fibers expressed the fast isoform of myosin, 44% slow isoform and 0.6% both. These findings allow three conclusions, Hagege said. "We can now say that the graft is still live, 18 months later, that it probably contributes to the improvement in the patient's heart function, and that there is some change in the phenotype of the cells in their new environment."

He said that because all 10 patients in the trial also had undergone CABG procedures at the same time as cell therapy, it was difficult to tell to what extent the observed improvement in the function of their hearts was due to the bypass procedures and what was due to cell therapy. However, the Phase II trial is designed to answer that question. The 300 patients who take part will be randomized to receive either a placebo injection or an injection of their own skeletal muscle cells during the bypass procedure.

Hagege and his colleagues are continuing with animal studies to try to find out whether the grafted cells themselves contract or whether they increase contraction of surrounding tissue in indirect ways.

EU medicines directive can affect coated stents

At the European Commission in Brussels, Belgium, there may be changes in definitions of "medicinal products" which could alter the status of existing medical devices such as heart valves, stents and catheters which incorporate biological coatings of human origin. The Directorate-General Enterprise (Division F2) that specializes in the medicinal sector is reviewing modifications to the definition of "medicinal products" and Annex A of the directive on Medicinal Products for Human Use.

The latest interpretation of the draft text is that it will reinforce or maybe widen the range of healthcare products that are covered. In particular, the proposed text for the definition could change the regulatory status of some medical devices so that the revised directive would apply to heparin-coated cardiovascular devices or antibiotic-coated catheters where the medicinal product is ancillary to the primary action of the device.

Some new cell-therapy products of human origin might be regarded as falling within the directive if they are based on the administration of cells rather than the primary mode of action, widening the range of healthcare products within its scope.

New CAD therapy

Schering (Berlin, Germany), together with its Collateral Therapeutics (San Diego, California) subsidiary, is developing intracoronary angiogenic gene delivery as a novel therapy for the treatment of coronary artery disease (CAD) in cases when bypass or stent surgery is contraindicated. The technique consists of the nonsurgical gene delivery of growth factor genes by intracoronary injection, which can be performed at the time of the diagnostic procedure.

According to John Warner, vice president of research and technology at Collateral Therapeutics, it is suitable for all patients, including those with impaired left ventricle function in whom a surgical procedure would be risky. Reporting on a Phase I study of Angiogenic Gene Therapy (AGENT) for patients with stable angina pectoris, Warner said that results showed there were no changes in heart rate or blood pressure during therapy administration and that growth factor genes reached the venous blood in one hour in the higher-dose group. There was measurable antibody response in most patients and no evidence of undesirable angiogenesis. Phase II trials have already started.

"Every minute one person dies of coronary artery disease," said Warner. "CAD accounts for 25% of deaths in people over 65, and half the deaths in the U.S. can be attributed to primary and secondary manifestations of CAD. In addition, more than 7 million people suffer from angina." Although 1 million bypass or stent surgeries are carried out each year in the U.S., they are not suitable in every case. On the other hand, medical therapy can be ineffective or intolerable.

Balloon angioplasty in Denmark

The DANAMI study in Denmark showed that there were greater benefits from transporting a coronary thrombosis patient up to 150 kilometers to a specialized cardiac center that could perform balloon angioplasty, in comparison with admitting the patient to a local hospital for treatment by thrombolytic therapy. As a result, the Copenhagen County Authority has allocated $4 million for the expansion of the heart center at Gentofte Hospital (Copenhagen, Denmark). The total expenditure for the resultant countrywide increase in the frequency of this procedure is projected at $14.5 million.

New hemocompatible coatings

Hemoteq (Wurselen, Germany) has developed a drug-eluting system, Ouverture, which combines hemocompatibility with the prevention of restenosis and which consists of two coatings. The first is Repulsion, a coating with a matrix for the continuous release of medication to reduce the occurrence of restenosis. The second is Camouflage, a permanent hemocompatible coating which serves to camouflage the synthetic surface, thereby reducing the tendency for blood clots to form.

The company envisions the use of the Ouverture two-coating system on stents, cardiac valves, artificial hearts, synthetic bypasses, tubing systems and catheters.

PolyBioMed (Sheffield, UK) has reported development of a copolymer coating for coronary stents where it is possible to modify the hydrophilic/ hydrophobic ratio. This can be useful for the manufacturer, since the coating can be tailored to suit a particular drug and the desired drug-release kinetics.

Gendel uses blood cells for drug delivery

A spin-off in 1998 from the University of Ulster (Ulster, Northern Ireland), Gendel (Coleraine, Northern Ireland) is working on the delivery of drugs to specific sites in the human body by using the red blood cells as a carrier.

"The cell is basically an empty bag, and it can go anywhere in the body," said Les Russell, CEO at Gendel. "This gives us the ability to deliver high doses (of drugs) at specific sites."

A sample of about 20 ml of a patient's blood is taken and the cells sensitized for loading with a drug (small molecule, oligonucleotide or antibody) using a high electric current. After reintroducing the blood cells to the patient, ultrasound is used to release the drug at the target site.

Proof of concept already has been obtained, Russell said, and Gendel plans various applications such as vascular disease, inflammation and oncology including the treatment of liver metastases.

Caffeine does not increase blood pressure

There is considerable controversy as to whether caffeine affects blood pressure levels. Robert Coti at University Hospital (Zurich, Switzerland) has investigated the effect of normal or decaffeinated coffee on blood pressure. Students taking part in the study were provided with expresso or decaffeinated coffee without knowing which they drank.

Both groups showed equal neurostimulation, but with no effect on blood pressure. Corti is continuing his research for another substance in coffee that can have the effect of increasing blood pressure levels.

Minisensor warns of MI risks

Researchers at the University of Basel (Basel, Switzerland) have collaborated with the IBM Research Laboratory in Zurich to develop a sensor for two blood proteins as biomarkers for an increased risk of myocardial infarction (MI).

The sensor, which detects creatine kinase and myoglobin, reacts to increased levels which can indicate possible heart muscle damage. The sensor, which is only 500 nanometers thick, detects any significant rise in risk within 10 minutes and provides an optical signal.

New indications for Plavix

Sanofi-Synthelabo (Paris) reported obtaining in the U.S. and Europe clearance for Plavix/Iscover (clopidogrel hydrosulfate) for therapeutic use in patients suffering from an acute coronary syndrome (myocardial infarct without Q wave).

The company also has registered in Europe and launched in the U.S. Arixtra for the prevention of venous thromboembolic events in patients after major orthopedic surgery. Such surgeries include hip fractures or implantation of hip or knee prostheses, Sanofi-Synthelabo said.