Cardiovascular disease (CVD) is the largest cause of mortality in the world, before cancer and infectious diseases. World Health Organization statistics for 2008 show that close to one in three deaths (29 %) in the world is due to CVD, representing more than 17 million per year. Cardiac diseases represent around 60 % of CVDs and are the single largest cause of death in the CVD population. Cardiac diseases can be broadly divided into diseases linked to blood flow to the heart muscle (ischaemic causes) and other diseases grouping together various causes that are not linked to the impairment of the blood flow to the cardiac muscle (non-ischaemic causes), such as hypertension, valvular dysfunctions and congenital and metabolic disorders. If left untreated, most cardiac diseases lead to heart failure (HF). HF is a common, costly, disabling and potentially deadly condition affecting 5.8 million people in the US1 and at least 15 million people in the European Society of Cardiology (ESC) countries.2 In the US, an estimated US$39.2 billion was spent on HF in 2010.3 While some advances in treatment have been recorded in this area, they remain limited and, with the exception of heart transplant, there is currently no cure for HF: “… a person living to age 40 years has a one in five risk of developing heart failure and, once the disorder is apparent, a one in three chance of dying within a year of diagnosis”.4 Another burden placed on society that cannot be understated consists of acute myocardial infarction (AMI) – the classic ‘heart attack’. It has been estimated that 11.8 million people suffer from an acute event every year.5
Cells as Biologics for Cardiac Repair
The scale of this unmet medical need emphasises the need for radically new approaches, such as cell therapy, to address the underlying cause of the disease – i.e., the loss of functional myocardium. It was in this context that Cardio3 BioSciences was founded in 2004. Cardio3 BioSciences is a leading Belgian biotechnology company focused on the discovery and development of regenerative and protective therapies for the treatment of cardiac disease. The company’s lead product candidate, C3BS-CQR-1, is a highly innovative cell therapy approach for the treatment of HF.
The technology behind the C3BS-CQR-1 cell therapy, which is described in greater detail later in this article, was licensed from Mayo Clinic (Rochester, MN, US) and comprises the programming of adult stem cells into cardiac progenitor cells, using natural signals replicating the signalling pathways leading to cardiogenesis during embryo development.
The underlying rationale behind this approach is that, in order to reconstruct cardiac tissue, stem cells need to be specific to cardiac tissue. The body’s self-repairing organs, such as bones or the liver, have many organ-specific stem cells, while the heart and other non-self-repairing organs harbour far fewer of these organ-specific stem cells. The key is therefore to provide cardiac-specific progenitor cells to the failing heart to induce cardiac repair.
Cardiopoiesis – Generating Cardiac Precursor Cells to Rebuild Heart Tissue
Research carried out at Mayo Clinic and in collaboration with the Cardiovascular Centre in Aalst (Belgium) uncovered the mechanism in the embryo that makes an embryonic stem cell become a heart cell.6 This led to the identification of a ‘cardiopoietic cocktail’ signalling the transformation of adult stem cells into cardiac progenitor cells, and to the development of Cardio3 BioSciences’ technological platform. The platform is designed to reprogramme the patient’s own stem cells into cardiac progenitor cells, to help rebuild the heart. The signalling used to perform this reprogramming is very different from the signals used to generate induced pluripotent stem cells (IPSCs), for example, where the mechanism relies on genomic modification. The processes used by Cardio3 BioSciences in its cardiopoiesis platform rely solely on factors (proteins and cytokines) that activate through binding to cell receptors and activating a differentiation sequence without permanently or temporarily modifying the genome of the cell.
The developmental biology knowledge underlying cardiopoiesis has also allowed the addition of other therapeutic development programmes, such as protein-based approaches to push the body’s innate repair mechanisms in indications such as AMI and cardiomyopathies (ischaemic and non-ischaemic). Stem cell-based therapies, whether through transplanted cells or directing innate repair, may provide regenerative approaches to cardiac diseases by halting, or even reversing, the events responsible for progression of organ failure.
The concept of applying stem cell therapy to repair a failing heart is rather simple: cardiopoietic cells are introduced into a damaged area of the heart, where they get embedded into the tissue and start to produce proteins that signal angiogenesis and myogenesis. The reality, however, is more complex, as the transplanted cells must be guided into the three-dimensional structure of the heart and the stem cells have to become cardiac cells in order to engraft and participate in the heart contraction.
The challenge is thus to provide the injured heart with stem cells that have the capacity to act as if they were cardiac-specific progenitor cells. Another critical factor for a permanent effect, either on endogenous cell stimulation or permanent transplantation, is that those cells need to remain in place for a relatively long, defined critical period.
It is this issue that has hindered the use of allogeneic approaches. While being appealing from a business perspective, allogeneic approaches are plagued by the fact that although mesenchymal stem cells may have a certain degree of immunoprivilege, they certainly lose that capacity as they become more mature cardiac progenitor cells and start expressing the major histocompatibility factors.7 They thus fail to trigger long-term changes in the damaged heart.
Cellular and Acellular Approaches – Targets and Current Clinical Status
The proprietary cardiopoiesis technology platform has generated a number of research programmes and product candidates, both cellular and acellular. The lead product candidate C3BS-CQR-1 is an autologous cell-based therapy targeting HF. It is designed to direct the patient’s own stem cells into cardiac progenitor cells with the potential to rebuild the heart.
Cellular
C3BS-CQR-1 is the first product candidate offering the potential for heart muscle regeneration and is produced by taking a patient’s own stem cells and differentiating them into cardiac tissue progenitor cells that are injected into the hearts of patients suffering from HF to promote repair without carrying the risk of rejection inherently linked to allogeneic approaches. CQR-1 has three modes of action: two direct modes (proliferation, engraftment and terminal differentiation of the injected cells and vasculogenesis) and one indirect (paracrine stimulation of endogenous resident cardiac stem cells and neoangiogenesis). A Phase II trial included 45 patients with ischaemic chronic HF who were treated with either cell therapy plus the best standard of care, or just best standard of care. In this way, the preclinical proof-of-concept findings have been extended to a clinical trial, meeting feasibility and safety objectives and addressing functional and clinical endpoints.
Acellular
Drawing on its understanding of the processes involved in cardiopoiesis, Cardio BioSciences has formulated protein-based product candidates which are aimed at protecting heart tissue from acute injury and promoting activation of resident cardiac stem cells in an AMI setting (C3BS-GQR-1). A preclinical study of C3BS-GQR-1 showed a 65 % decrease in scar size at six weeks post-infarction compared with a 25 % decrease in scar size following a placebo injection. An analysis of the animals’ hearts confirmed that the therapy worked through the stimulation of resident cardiac cells by the protein factors.
Conditioned media (C3BS-GQR-2) and lyophilised solutions (C3BSGQR- 3) are other methods currently in preclinical trials aiming to use the secretome of cardiopoietic cells to induce self-regeneration through the activation of cardiac stem cells. C3BS-GQR-4 is an antibody-based therapy targeting the warm reperfusion injury mechanism at the basis of the inflammatory response in both AMI and chronic ischaemic cardiomyopathies.
Conclusion
Regenerative therapies are a paradigm shift in medicine. Although the approach is more complex than traditional pharmaceuticals, the potential of such therapies is unique in the sense that they target organ repair versus the treatment of symptoms. This offers new opportunities for curative treatments in cardiac diseases, among others, and thus for more effectively tackling one of the leading causes of mortality in the world. However, the novelty of new cell therapies implies that their development requires specific skills, new tools and new methods. They pose considerable challenges in production and logistics, among others. For any of these therapies to reach patients, many challenges have to be tackled during preclinical and clinical development and, during the manufacturing of highly personalised products, scaling up, supply chain and, very importantly, distribution. The promise is beginning to be realised and encouraging preclinical results have been generated, which take us closer to providing an additional therapeutic tool for physicians to use for their patients. The goal of the regenerative therapy industry is to increase the quality of life of patients suffering from very debilitating diseases. While significant progress has been made, this goal will only be achieved through perseverance and continuous innovation.