Ischaemic heart diseases, such as heart attacks and angina pectoris, are caused by the development of arteriosclerosis in the walls of the coronary arteries, which impedes the passage of blood to the heart muscle cells, representing one of the major causes of death for the population of more than 35 years in developed countries. In fact, it is estimated that 33 per cent currently causes of the same.
This represents an incidence of 1 out of every 3 people in this age range, so it is clear the urgent need for preventive measures and develop new therapies that constitute increasingly effective treatments and less invasive, representing less risks and adverse effects and increasing the quality of life of patients.
The regeneration of the infarcted heart tissue is one of the ways in which up until now have not been referred to, since the reinstatement of the cardiac circulation has been carried out usually by surgical methods such as coronary artery bypass surgery or the implantation of devices such as percutaneous revascularization through stents.
Let’s take a look at each one treatment and let’s discover what new horizon in the area of regenerative medicine therapies reveals us a new advanced therapy developed by the German company Viscofan.
Treatment of ischaemic heart disease:
Due to the fact that atherosclerosis is caused by the accumulation of collagen, fat and inflammatory cells (lymphocytes) in the walls of the coronary arteries, which thickens and comes to prevent the passage of blood to the heart muscle cells (myocardium), this causes that diminish their cell functions and tissue as a whole, as in angina pectoris, or coming to kill the cells of the myocardium as in heart attacks, in which the occlusion of the artery is total.
As a treatment, until now the therapies have consisted in the combination of surgical operations, drug treatments (vasodilators, betablockage, antiplatelet drugs) and change of habits of life: quit smoking, exercise, good nutrition.
The surgical treatments may be in the form of device implantation in the affected areas, in cases of angina pectoris, to widen the light of the arteries and allow the passage of blood, such as percutaneous revascularization through stents (metal empty cylinders), or by coronary bypass that sews a vein or artery from the patient himself parallel to the diseased vessel, without touching the area that is fully blocked.
For the bypass also can be used an artery of the patient himself, called internal mammary vein, which is extracted from the legs.
Are also used as treatment, although high-risk, the heart transplants.
To avoid the risks of open heart surgery and the complications inherent to the processes of healing, that develop after application of stents, and the realization of coronary bypass:
Why not develop a natural biodegradable patch where to grow stem cells to regenerate the myocardium, and that through its stitches in the affected area to reconstitute damaged tissues.
This task is what has been proposed to carry out the German company Viscofan, through its biomedical unit Viscofan BioEngineering which is leading this project called Cardiomesh.
Its preclinical development, its phases of manufacture and the conduct of clinical trials are developing entirely in different centers pioneers of Spain.
In this way their preclinical development has been conducted by researchers at the University Hospital of Navarra and the Center for Minimally Invasive Surgery Jesus Usón in Cáceres.
Its phases of obtaining certification GMP (Good Manufacturing Practices), necessary for the manufacture, sale and use in the subsequent trials of this novel Advanced Therapy ( Advanced Therapy Medical Product, ATMP), which has a special regulatory framework, has been developed successfully by the Navarrese company 3P BioPharmaceuticals.
3P Bio In fact constituted the first spanish company producer of biopharmaceuticals, whose impact at the level of the national health system of these medications and their biosimilars you can view here.
In its clinical trial phase I, which is currently being developed, are involved the Hospital Gregorio Marañón in Madrid and the University Hospital of Navarra.
Let’s take a look at what consist this new Advanced Therapy and how it has been managed to develop in a pioneer manner.
Advanced Therapy CB-C01:
The Therapy CB-C01, developed within the project Cardiomesh, is based on the combination of allogeneic stem cells from adipose tissue (ADSC, adipose derived stem cells), cultured from a donor or compatible cell line, planted over a carrier collagen membrane of cells (CCC, Collagen Cell Carrier) that promotes tissue regeneration of damaged myocardium.
With regard to the allogeneic stem cells from adipose tissue, as explained by Dr. Jesus Benito, medical director and founder of Antiaging Group Barcelona, «they are not capable of forming a whole organism or differentiated themselves in any tissue as embryonic stem cells, but in the laboratory they have been able to achieve creating fat cells, cartilage, muscle, bone, endothelial cells, hepatocytes and hematopoietic (from bood).
The ADSC are easy to obtain in large quantity of adipose tissue and can be grown in the laboratory by increasing their number. One gram of adipose tissue has 700,000 stem cells. This has made them the main resource for researchers in the progress of the so-called regenerative medicine. Spontaneously are not converted in this type of cells, but they require a special culture or the addition of specific growth factors.
To obtain the lipoaspirate undergoes a process of enzymatic digestion and centrifugation. One gets a small deposit called Stromal Vascular Fraction (SVF) in which there are macrophages, endothelial cells, lymphocytes T and the ADSC. This SVF is treated so that we can get the ADSC.
To differentiate them are identified markers. The ADSC are characterized by having a few markers that are CD34+, CD31- and CD45-. The endothelial cells are CD 31+ and hematopoietic cells are CD145+.
The first action of the ADSC is to become endothelial cells when conditions are poor in oxygen (hypoxia).
Various investigations in particular situations where the tissues heal poorly due to poor vascularization (inadequate blood supply and therefore oxygen), treatment with stem cells improves the situation and helps repair tissue in: ulcers, fistulas in Crohn’s disease (an inflammatory disease that affects the ileum and colon), radiodermitis (sequel to radiation therapy), ischemia of the extremities (vascular diseases of limbs) and myocardial infarction.
The Adsc also have an anti-inflammatory effect and act as an immunomodulating agents, as well that they are being investigated in Alzheimer’s Disease, osteartrosis and osteoarthritis and graft-versus-host of transplants. It has been shown that the ADSC when injected intravenously are directed to the affected area (inflamed) to perform its job.»
In this way, in CB-C01 these cells are attached to the natural collagen biodegradable membrane, forming a strong bond of their cellular arrays. Subsequently, the membrane is sutured during a surgical intervention directly to the site of the damaged tissue.
Consideration is being given to the implementation of the membrane using laparoscopy, which would considerably reduce the invasiveness and the risks associated with the open heart surgeries. These investigations are being carried out in sheeps, as they have a chest similar to human.
In vivo experiments during the preclinical phases, developed in mice and pigs, since in the latter the heart and the development of arteriosclerosis are similar to the human model, have shown that the membrane produces an increase in the cellular retention at the site of implantation and a consistent improvement of function of the tissue, increasing by 15% the recirculation in areas that had led to loss of tissue by ischemic cell death (Biomaterials Spider et al., 2014).
In terms of immunogenicity, the results so far have been encouraging since it only develops mild immune reactions on the part of the tissue of the host.
In the 1990s Viscofan begins to show their concerns in the area of biomedicine, since this company initially had already succeeded in becoming the leader in more than 100 countries around the world in the production of casings of different materials, including collagen, for the meat industry.
Because of the ubiquity of collagen in the greater part of living tissues and its structural functions and its role in the regeneration of these, through the creation of its unit Viscofan BioEngineering has been established research collaborations with academic institutions such as the University Eye Clinic in Aachen, the Urology Department and the Institute of Anatomy in Tübingen, Germany, or the University of Navarra – CIMA, Pamplona, Spain.
Through these collaborations verifies the characteristics and functions in -vivo of its collagen cells carrier membrane (CCC) for use as a treatment in medical indications of different diseases: from the heart, vision, urologic, intestinal and skin disorders.
In 2008 is when Viscofan takes the step to contact the Clinic University of Navarra and the Center for Applied Medical Research (CIMA). It is then the team of the Researcher Felipe Prósper (University of Navarra Clinic) which successfully developed the research for the cultivation of allogeneic stem cells on the membrane of collagen.
The preclinical study in pigs and rats was carried out at the University of Navarra and the Center for Minimally Invasive Surgery Jesus Usón in Cáceres. Consisted in inducing the infarction to animals and then applying the drug, and improving the vascularization of the damaged areas (chronic and advanced of ischemic origin), thus increasing the exhaust oxigen recirculation, as has already been discussed above a 15%.
In 2015 Viscofan contacts 3P Biopharmaceuticals, a company specialized in the manufacture of biopharmaceuticals, which becomes responsible for developing the industrial process for injecting stem cells in the membranes of collagen (a process called cellular).
See more in detail this collaboration between these organizations.
3P Biopharmaceuticals, Is a biotechnology company CDMO (Under Contract Development and Manufacturing Organization) specialized in the development and manufacturing processes of biological medicinal products and products of cell therapy for preclinical phases of clinical trials and marketing for other companies under conditions of GMP (Good Manufacturing Practices).
It has a division of cell therapy in that first develops the implementation and commissioning of the process, and then scaling of the production and validation in GMP (Good Manufacturing Practices).
With the GMP certification, 3P Bio is able to expand the adoption GMP for the production and sale of: active biological substances, the sale of biological medicinal products, of sterile products for human and veterinary use, and of medicinal products in research to be used in clinical trials.
On the other hand, 3P Biopharmaceuticals is a pioneer in the production of stem cell cell banks designed to allogeneic use in Spain.
In this way, it is one of the few organizations that has the know-how to manage co-development projects and manufacturing for third parties from stem cells and somatic cells of different tissues. All this makes the company is currently involved in the development of other projects of advanced therapy for the treatment of different diseases.
Two years after this successful partnership, in December 2017, the AEMPS conducted an audit of the production process to 3P Biopharmaceuticals, certifying compliance with the Rules of Good Manufacturing Practice (GMP), necessary for the biopharmaceutical production and its application in humans for the new Advanced Therapy .
The past 14 May 2018, the AEMPS authorized the biomedical unit Viscofan, Viscofan BioEngineering, the begining of the human clinical trials of the project Cardiomesh.
The Deputy Director of R&D of Viscofan Group, Blanca Jauregui Arbizu, foresees that they can begin with the clinical tests after summer in the Gregorio Marañón Hospital in Madrid and at the Universitary Navarra Clinic. The intervention consists on an open-heart surgery in which to place the patch of collagen membrane with the allogeneic stem cells in the infarcted area.
It is currently in phase of search for patients with ischemic heart disease and dysfunction of the left ventricle to be enrolled in the clinical trial.
In this phase I clinical trials they evaluate the efficacy and safety of the product. The evolution of the patient will be follow for one year.
To do this the Spanish Ministry of Economy has given a fund of 1.26 million € to the project Cardiomesh. The funds will be used primarily for the development of the phase I clinical trial evaluating the safety and efficacy of VB-C01, this new cell therapy to treat patients with heart failure.
The clinical development has the same protocol that of a drug.
On the other hand Viscofan destines 1.5 million annually to the development of this therapy since its inception.
Researchers involved:
Felipe Prósper (University of Navarra Clinic) Beatriz Pelacho, researcher at the top; Enrique Andreu, of the University of Navarra Clinic; Juanjo Gaviria, a cardiologist from the University of Navarra Clinic; Ana Casado, a cardiologist in Viscofan but that her physical headquarters is currently in the Hospital Gregorio Marañón; the cardiologist Paco Fernández Avilés, Javier Bermejo and Veronica Chrysostom (the latter in the center of Cáceres).
You want to know more:
Atherosclerosis is a process that begins in the first decades of life, but no symptoms are presented until the stenosis of the right coronary artery becomes so severe that causes an imbalance between oxygen supply to the myocardium and their needs. In this case, there is a myocardial ischemia (stable angina pectoris) or a sudden occlusion due to thrombosis of the artery, causing a lack of oxygenation of the myocardium that gives rise to the acute coronary syndrome (unstable angina and acute myocardial infarction).
Image credits: Yurchanka nobeastsofierce Arthimedes SIARHEI,,, crystal light / shutterstock.com
References:
http://www.viscofan-bioengineering.com/applications/regenerative-therapies-atmps