Science Pool

Autoimmune diseases (ADs) represent a significant challenge in healthcare, affecting millions worldwide. These conditions arise when the body's immune system mistakenly attacks healthy tissues, leading to chronic inflammation and tissue damage. While current treatments for ADs focus on immunosuppression, they often come with significant side effects and provide only symptomatic relief. In recent years, there has been growing interest in cell-based therapies, particularly CAR (chimeric antigen receptor) cell therapy, as a potential solution to address the underlying causes of ADs.  

Autoimmune diseases encompass a wide range of conditions, including rheumatoid arthritis, lupus, multiple sclerosis and inflammatory bowel disease, among others. Despite their diverse manifestations, these diseases share a common underlying pathology of immune dysregulation. In healthy individuals, the immune system is finely tuned to distinguish between self and non-self antigens, but in autoimmune disorders, this distinction becomes blurred, leading to an attack on the body's own tissues. 

CAR cell therapy offers a promising approach to treating ADs by depleting disease-driving immune cells and rebalancing immune homeostasis. CAR T cells, which are engineered to express synthetic receptors targeting antigens expressed on the surface of pathogenic cells, have shown remarkable success in treating certain cancers. Now, researchers are exploring the potential of CAR T cells and their counterparts, CAR iNK (natural killer) cells, in targeting the aberrant autoreactive cells implicated in autoimmune diseases to reset the immune sytsem¹. We believe that cell therapy approaches could provide long-lasting drug-free remission and potentially a curative treatment for AD patients.

Understanding CAR Therapeutics

CAR T cell therapy first emerged as a groundbreaking treatment modality for hematological malignancies, such as leukemia and lymphoma. Building on this clinical success, researchers have recently turned their attention to applying CAR cell therapy to treat autoimmune diseases. 

In the context of ADs, CAR T cells have been investigated for their ability to target autoreactive T cells or B cells. B cells, in particular, play a central role in many autoimmune disorders by producing autoantibodies and driving inflammation. One promising target for CAR cell therapy in ADs is the cell surface protein CD19. High-level expression of CD19 is maintained throughout the majority of B-cell differentiation stages. By targeting CD19-positive B cells, CAR T cells or CAR NK cells can selectively eliminate the autoreactive B cell populations responsible for driving autoimmune responses². 

A recent early clinical study showed promising results for using CD19 CAR T cell therapy to treat ADs. Patients with systemic sclerosis, severe Systemic Lupus Erythematosus (SLE), and idiopathic inflammatory myositis showed remission following therapy³. However, CAR NK cell therapy may be beneficial over CAR T cell therapy, particularly in ADs that have dysfunctional T cells. CAR T cell therapy may also result in side-effects such as GvHD (Graft-versus-host disease, worsening the AD symptoms), neurotoxicity, and cytokine release syndrome; CAR NK cell therapy may offer a safer alternative⁴. 

Despite the potential of CAR cell therapy in ADs, several challenges remain, including scalability, persistence, and off-target effects. Evotec's innovative approach to addressing these challenges involves the use of induced pluripotent stem cells (iPSCs) to generate allogeneic off-the-shelf CAR iNK cells with enhanced scalability and precision. iPSCs, reprogrammed from adult somatic cells, offer a potentially inexhaustible source of immune cells that can be genetically engineered and differentiated into various cell types to tackle a range of diseases.

iPSC-Derived CD19 CAR iNK Cells for Targeted B Cell Depletion

A study by researchers at Evotec investigated the performance of iPSC-derived CD19 CAR iNK cells as a novel therapeutic approach for ADs. Using Evotec’s validated GMP iPSC line, researchers produced genetically modified cells with a knock-in of CD19-CAR. The modified cells successfully differentiated into CD19 CAR iNK cells using a feeder-free 3D differentiation process, which could be confirmed by flow cytometry. The established protocol can ensure high purity and functionality of the resulting cells. Results showed that iNKs generated from the GMP iPSC line were homogenous and phenotypically comparable to blood-derived (BD) NK cells form healthy donors.  

Figure 1: Cytotoxicity against SLE patient B cells. NK killing assays of effector cells - iNK without CAR (WT), CD19 CAR iNK or healthy donor BD NK cells (BD-NK) co-cultured 1:1 (E:T) with SLE patient B cells, + 10μg/ml anti-CD20 antibody (Obinutuzumab (Obi)) or isotype control (Iso) (n=2). 

In vitro experiments demonstrated the cytotoxic effector function of CD19 CAR iNK cells in selectively targeting and eliminating CD19-positive B cells. Co-culture assays using patient-derived primary B cells from patients with SLE autoimmune disease, showed robust cytotoxicity of CD19 CAR iNK cells. The CD19 CAR iNK cells were more efficient than iNK cells without a CAR or BD NK cells in depleting the patient-derived primary B cells. These findings highlight the therapeutic potential of CD19 CAR iNK cells in treating ADs, offering a targeted and scalable alternative to conventional immunosuppressive therapies.

Evotec's Scalable Therapeutics Approach

Evotec's commitment to allogeneic cell therapy innovation is exemplified by its scalable therapeutics approach, which leverages cutting-edge technologies and infrastructure to develop next-generation therapies for ADs. Central to this approach is the use of iPSCs as a platform for generating CAR iNK cells with enhanced scalability and precision. By introducing CARs targeting CD19 into iPSCs and differentiating them into iNK cells, Evotec aims to create scalable and precise off-the-shelf therapies for ADs. 

Figure 2: Evotec’s pipeline to co-create iPSC-based cell therapeutics with partners in Inflammation & Immunology.

Evotec's end-to-end process for iPSC-based therapeutics encompasses differentiation, gene editing, preclinical and clinical development, ensuring the efficient generation and characterization of CAR iPSC-derived cells. By utilizing validated GMP iPSC lines and GMP-compatible differentiation protocols, Evotec ensures the safety and quality of its allogeneic cell therapy products, paving the way for clinical translation.

Figure 3: Evotec’s end-to-end process for iPSC-based therapeutics. 

The scalability of Evotec's approach enables the production of large quantities of CAR iNK cells, making them suitable for widespread use in treating ADs. Additionally, the precision of iPSC-derived CAR iNK cells allows for targeted and personalized therapies tailored to individual patients' needs, reducing the risk of off-target effects and enhancing treatment efficacy.

Future Potential with Evotec

Evotec's iPSC-derived CD19 CAR iNK cells represent a promising new approach to treating autoimmune diseases. By harnessing the power of iPSC and CAR technology, allogeneic cell therapy can help revolutionize the treatment landscape for ADs, offering patients a targeted, scalable and potentially curative alternative to conventional therapies. 

As research in this field continues to advance, Evotec remains at the forefront of allogeneic cell therapy innovation, driving the development of next-generation treatments for ADs (Figure 2). Evotec’s GMP-compliant production pipelines provides an efficient, reproducible, and scalable way to produce CAR iNK cells derived from iPSC for clinical development. With its commitment to precision medicine and scalable therapeutics, Evotec is well-positioned to meet the growing demand for effective and accessible off-the-shelf therapies for autoimmune diseases.

See more iPSC-based Cell Therapies for I&I Diseases

To discover more about this research, download our scientific poster

References: 

(1) Blache, U.; Tretbar, S.; Koehl, U.; Mougiakakos, D.; Fricke, S. CAR T Cells for Treating Autoimmune Diseases. RMD Open 2023, 9 (4), e002907. https://doi.org/10.1136/rmdopen-2022-002907.

(2) Jin, X.; Xu, Q.; Pu, C.; Zhu, K.; Lu, C.; Jiang, Y.; Xiao, L.; Han, Y.; Lu, L. Therapeutic Efficacy of Anti-CD19 CAR-T Cells in a Mouse Model of Systemic Lupus Erythematosus. Cell. Mol. Immunol. 2021, 18 (8), 1896–1903. https://doi.org/10.1038/s41423-020-0472-1.

(3) Müller Fabian; Taubmann Jule; Bucci Laura; Wilhelm Artur; Bergmann Christina; Völkl Simon; Aigner Michael; Rothe Tobias; Minopoulou Ioanna; Tur Carlo; Knitza Johannes; Kharboutli Soraya; Kretschmann Sascha; Vasova Ingrid; Spoerl Silvia; Reimann Hannah; Munoz Luis; Gerlach Roman G.; Schäfer Simon; Grieshaber-Bouyer Ricardo; Korganow Anne-Sophie; Farge-Bancel Dominique; Mougiakakos Dimitrios; Bozec Aline; Winkler Thomas; Krönke Gerhard; Mackensen Andreas; Schett Georg. CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-Up. N. Engl. J. Med. 2024, 390 (8), 687–700. https://doi.org/10.1056/NEJMoa2308917.

(4) Műzes, G.; Sipos, F. CAR-Based Therapy for Autoimmune Diseases: A Novel Powerful Option. Cells 2023, 12 (11), 1534. https://doi.org/10.3390/cells12111534.

Inflammatory Bowel Disease (IBD) is the umbrella term for a group of diseases characterized by chronic, idiopathic and remitting inflammation of the gastrointestinal tract. Common symptoms include diarrhea, abdominal pain, and fatigue. However, extraintestinal manifestations such as inflammatory arthralgias/arthritides, primary sclerosing cholangitis (PSC), ocular or cutaneous involvement are often present and add to the complexity of the clinical picture.

The two most common forms of IBD are Crohn's disease and ulcerative colitis. Crohn's disease can cause inflammation anywhere in the gastrointestinal tract from the mouth to the anus, while ulcerative colitis is usually confined to the colon, where it can cause inflammation and ulceration. In about one in ten people, the two diseases cannot be clearly distinguished, and the condition is called indeterminate colitis. With approximately 6-8 million IBD patients worldwide (2 million in Europe and 1.5 million in North America), there is a huge unmet medical need.

IBD is an immune-mediated disease, but the exact causes are unknown. Crohn's disease, for example, involves a complex interplay of genetic predisposition, immune dysregulation, environmental influences, and microbial factors.

This complexity poses many challenges for drug development, as exemplified by the recent failure of a drug approved for ulcerative colitis that failed in late-stage clinical trials for Crohn's disease. The important lesson here is the need for proper patient stratification.

With its multimodal approach and patient stratification tools, Evotec is well positioned to develop innovative medicines. The Company is focused on development of IBD medicines through in-house research and through collaborations. Evotec’s strategy is modality agnostic, utilizing Evotec’s entire scope of technology platforms - from small molecules to biologics as well as iPSC-based cell therapies.

The Evotec approach

Drug discovery at Evotec always starts with patient data. Evotec's drug discovery efforts are based on its proprietary panOmics approach and a proprietary portfolio of molecular patient databases (E.MPD). panOmics combines both data generation and analysis platforms to industrialize OMICs data generation and AI/ML-based omics data analysis. Based on proprietary molecular patient data, panOmics fundamentally improves the understanding of disease processes, in vitro and in vivo disease modeling, identification of novel high value targets, biomarker discovery and patient selection.

Another integral aspect of drug development at Evotec is precision medicine. For this approach, Evotec has developed a comprehensive patient stratification toolbox via its panOmics-driven diagnostic approach – EVOgnostic.  

Therefore, IBD patients are an integral part of a pilot study in which Evotec is performing plasma and metabolomic analyses on samples from autoimmune disease patients to combine these clinical data with experimental data and data science approaches to identify potentially novel biomarker signatures.

Evotec aims to develop medicines that allow an early intervention and or, ideally, a cure for patients suffering from IBD. Evotec is engaged in several drug discovery programs tackling various aspects of IBD such as restoration of epithelial barrier function, modulation of inflammation, or resolution of intestinal fibrosis. Depending on the different aspects of the disease. Evotec’s experts are engaged in the IBD community and you can see our recent poster summarizing our IBD activities here. 

Selected collaborations

Evotec also is constantly seeking to enhance its capabilities through strategic investments and collaborations. For example, in 2022 it invested in IMIDomics Inc., a company focused on immune-mediated inflammatory diseases (IMIDs). IBD constitutes a large part of IMIDs. The aim is to jointly develop and use IMIDomics' Precision Discovery™ Engine. This technology enables a deep understanding of how inflammatory diseases work in patients. It applies a combination of clinical and computational expertise to clinical data and biological samples from more than 17,000 patients in a biobank, generating proprietary biomolecular signatures. 

With the Crohn's & Colitis Foundation, Evotec is advancing drug discovery for two novel IBD drug targets originating from academic research. The targets address fibrosis, the excessive accumulation of scar tissue in the intestinal wall, and the restoration of intestinal barrier function in IBD to reduce the increased intestinal permeability and chronic intestinal inflammation often seen in IBD patients.

Efficacy models in IBD

Another challenge in IBD is the lack of adequate animal models. While more than two dozen mouse and rat models of colitis have been developed and implemented, the multifactorial etiology and highly heterogeneous manifestations of the disease have prevented the development of a model that fully represents the pathophysiology of human IBD and related complications. Each mouse model has its strengths in elucidating the pathogenesis of colonic inflammation, fibrosis, or CAC, but each has a self-limiting nature and shows marked variability in drug development. While these IBD models cannot fully recapitulate the disease features commonly seen in humans (genetic and environmental influences, gut microbiota interactions, etc.), they have led to the identification of three key elements for disease etiology: T lymphocytes (T cells) mediate chronic intestinal inflammation; intestinal inflammation is initiated and maintained by certain commensal intestinal bacteria; the onset and severity of the disease is largely dependent on the genetic background.

Therefore, Evotec has carefully selected several preclinical models that recapitulate key aspects of IBD: inflammation, leukocyte trafficking, breakdown of epithelial barrier integrity, T cell-mediated injury. These models are routinely used and complemented by the current gold standard: the T cell transfer model of chronic colitis. This mouse model best reflects the clinical pathology observed in IBD and dissects the initiation, induction, and regulation of T cell-mediated immunopathology. 

In summary, Evotec is advancing breakthrough solutions for IBD using the most advanced technologies and platforms available. The Company's primary focus is on precision medicine and leading-edge approaches with the goal of providing tailored, effective, and minimally invasive treatments by taking into account the unique characteristics of each patient.

Download our poster from the IBD Innovate Conference

IBD is a collective term for a range of clinical phenotypes caused by chronic, idiopathic and remitting inflammation of gastrointestinal tract. Crohn’s disease and ulcerative colitis are the two most common forms. Despite many advancements in the treatment of IBD, there remains a high unmet medical need to provide patients with an early intervention of highly effective therapy, preferably with curative potential. 

Evotec is currently engaged in several drug discovery programs tackling various aspects of the disease such as restoration of epithelial barrier function, modulation of inflammation and intestinal fibrosis.

Given the heterogeneity of the disease, we actively invest into efforts leading to increased disease understanding and stratification of patients based on the disease endotypes.

DOWNLOAD THE POSTER

Evotec possesses a comprehensive drug discovery platform to support oligonucleotide-based drug discovery from in silico design to clinical translation. Oligonucleotides therapeutics have been emerging as novel therapeutic modality for a vast range of diseases constantly growing resulting in 15 drugs currently approved. Here, we show our ongoing effort to further expand this platform by employing the recently developed splintR-qPCR as a novel bio-analytical method for quantification of oligonucleotides in tissues and comparing it to LC/MS and bDNA in use in Evotec. Within an Evotec internal R&D proof of concept study, the splintR-qPCR was proven as valid and comparable method to bDNA and gold-standard LC/MS. The high sensitivity, throughput and low costs compared to LC/MS and bDNA assay place splintR-qPCR as pivotal method that will strengthen Evotec oligonucleotides expertise on PKPD modelling.

Download our poster here!

About this Webinar

In this short recording, Dr Pia Thommes, VP Anti-Infectives and Virology Therapeutic Leader discusses:

• Current challenges in Infectious Diseases drug discovery
• Human SARS-CoV-2 and other emerging viruses
• Industry relevant in vivo models
• The wider reaching consequences of the COVID pandemic

More about Dr Pia Thommes.

Pia gained her PhD in Molecular Genetics and followed this with a postdoctoral in biochemistry, focusing on DNA replication and cell cycle. She has 12 years experience in drug discovery of antivirals at GW/GSK, 4 years work in oncology on DNA Damage Response at KuDOS/ AZ. In 2012 Pia took on a role as Scientific Operations Director at Euprotec, a specialist CRO for infectious disease, this was incorporated into the Evotec family in 2014. Currently Pia is working as VP of Anti-infectives in Alderley Park and also Therapeutic Area Lead for Virology.

Hope you enjoy the webinar

Watch the Recording Now

While the public has taken note of RNA-based medicine only with the advent of mRNA-based Corona virus vaccines, biopharmaceutical research and development has been working on mRNA-based medicine for almost two decades. Evotec also expanded the druggable target space to RNA and in the last years added considerable know-how in RNA-based medicine.

RNA is used by cells in multiple ways: mRNA is conveying genetic information from DNA to the ribosomes which also are made from RNA (ribosomal RNA), where another RNA species (tRNA) is transporting amino acids to the ribosomal apparatus so that a protein can be synthesized. In addition to mRNA, there are also shorter RNA molecules being used in the cell for the regulation of genes and entire genetic cascades.

This provides for plenty of potential interventions: antisense (ASO) and short interfering RNA (siRNA) can up or down regulate an RNA target, e.g., to block the translation of an unwanted or diseased protein or to suppress or stimulate the expression of genes. RNA can be targeted with (complementary) RNA, but it is also possible to alter or block the translation, re-locate or initiate RNA, degradation, etc. by small molecules interfering with the three-dimensional structure of RNAs or protein-RNA-complexes.

During our recent Innovation Week, Evotec experts Steffen Grimm, Group Leader, Hit ID & Biophysics, and Hilary Brooks, Senior Research Scientist, In Vitro Pharmacology, hosted a session called "The early bird catches the helix: Expanding the druggable target space to RNA".

In the session, they discussed how to:

• Expand the potential for drugs targeting RNA to offer alternative solutions for diseases with otherwise undrugged targets
• Target RNA providing highly specific solutions for protein removal, alternative splicing or pathway regulation via noncoding RNA
• Use the small molecule RNA targeting platform to contribute to new opportunities for target identification and validation

RNA as Therapeutics
Using RNA as therapeutics is not trivial. Nucleic acids introduced from outside may trigger adverse reactions by the innate immune system. A lot of knowledge is necessary to ensure delivery, avoid degradation and inflammation and to fine-tune the stability and function of the molecules. RNA may also have off-target effects. To ensure efficacy and safety, monitoring these early on needs to be incorporated into the developmental workflow. High quality synthetic RNA is costly to make, therefore a scaleable process and the relevant analytics must be established early in the process to accompany both the discovery and development stages of research with quality test material; Eventually producing GMP grade RNA at a commercial scale (several hundred grams) for human administration.

Evotec already has integrated all capabilities under one roof, allowing for the complete preclinical data set, reduced transition times and efficient communication to the regulators. For antisense oligonucleotide therapy, efficient hit sequences that knock down target expression can be selected in a matter of weeks. Toxicity profiling is a priority to establishing final leads and, subsequently, project-specific dose, duration and delivery will be established using optimized backbone chemistry. Using its in-silico capabilities as well as iPSCs, animal models, transcriptomics, etc. Evotec is able to predict toxicity and efficacy, and de-risk unwanted immune stimulation as well as off-target effects. For manufacturing, Evotec is discovery-capable and already building medium-scale capacity (up to 50g) which will be ready by 2023.

For inhibiting the translational machinery, Evotec has established an RNA small molecule targeting platform and established in various case studies, molecules binding to RNA, and demonstrating a significant effect in vitro without affecting cell viability. Evotec’s capabilities also allow the creation of a representation of the 3-dimensional structure of the target complex and its interaction with the compounds.

Evotec’s experienced team of scientists with proven drug discovery and development expertise already have a track record of driving RNA targeting projects forward. Its integrated medicinal and computational chemistry capabilities, combined with bioinformatics, structural biology, pharmacology, and drug safety expertise allows for the identification and characterization of RNA target species and their modulation by different modalities. Partner projects can be driven all the way from target identification to IND and beyond. Evotec therefore is a low-risk outsourcing partner and a company continually investing in its platform to the benefit of the customer.

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Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). In this recent article, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus

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Evotec strives to provide partners and customers with less expensive, faster, and more flexible approaches for discovering, developing and manufacturing biotherapeutics.

With the acquisition of Just Biotherapeutics in 2019, Evotec made a major push into biologics, and has successfully built a fully-integrated platform to drive monoclonal antibody (“mAb”) programmes from concept through to commercialisation. The company generates antibody lead candidates by providing access to in vivo and in vitro sources of antibodies, combined with state-of-the-art technologies to ensure success for a broad range of targets and disease states. In addition, if needed, selected lead candidates can be further optimised using powerful computational platforms such as Evotec’s proprietary Abacus™ in silico tool suite to enhance the productivity, but also ease of manufacturing and formulation stability.

For in vivo immunisation, Evotec is offering the ATX-Gx^TM mouse platform developed by its collaboration partner Alloy Therapeutics. This platform is a suite of immunocompetent transgenic mice for best-in-class in vivo discovery of fully human monoclonal antibodies. These mice are engineered to drive the greatest potential diversity and broadest epitopic coverage of unique human antibodies binding to a specific target of interest.

ATX-Gx^TM mice provide:

• a fully human heavy chain repertoire,
• human kappa and human lambda chain repertoire,
• haplotype diversity, and
• limited immunodominance.

Taken together, these immunocompetent transgenic mice represent the complete functional human antibody repertoire, and their fully functional, robust immune response is equivalent to the response of wild type mice. They are also available on multiple genetic backgrounds such as BALB/c or BL/6.

ATX-Gx^TM has been extensively validated and continuously expanded for more than 12 years and is currently used by over 75 antibody discovery groups in large biopharma and small-to-midsize biotech companies as well as academic research labs.

Following immunisation, Evotec is combining traditional hybridoma technology with automated devices for high throughput clone selection, screening, recombinant expression and purification to shorten and simplify the process of hybridoma establishment. Screening is performed with high-throughput technologies, such as the iQue® Advanced Flow Cytometry Platform. Next-generation sequencing is used to obtain VH/VL information, followed by an in silico analysis using Just – Evotec Biologics Abacus® software tool. Once VH/VL information is available, several hundred mAbs can be produced in parallel in small scale. This high quality material can then be used for further downstream characterisation, such as functional activities that allow the selection of potential lead candidates.

This streamlined workflow to generate high-quality antibody panels for functional assessment adds to Evotec’s comprehensive suite of large molecule discovery tools, disease biology, state-of-the-art cell line development, machine learning design tools, manufacturing, preclinical IND-enabling studies, as well as FIH clinical support, and commercialisation.

Evotec’s AI-driven antibody discovery can be accessed as stand-alone services or through Evotec’s seamlessly integrated antibody drug discovery platform

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Pneumonia induced by multidrug resistant (MDR) Acinetobacter baumannii strains is among the most common and deadly forms of healthcare acquired infections. Animal models play a critical role during the preclinical assessment of novel therapeutic approaches, however, only a self-limiting pneumonia with no or limited local bacterial replication is frequently obtained when MDR A. baumannii is the pathogen.

To strengthen and characterise a sustained lung infection model, in this publication, we focus on:

• the ability of intranasal inoculation, intratracheal instillation and oropharyngeal aspiration methods of administration of the bacterial challenge to induce a robust pneumonia in mice
• the characterisation of the infection model obtained after intratracheal instillation and oropharyngeal aspiration in terms of histopathological examination of pulmonary lesions, biomarkers of inflammation and leukocytes cells infiltration after treatment with either vehicle or with the antibiotic tigecycline efficacious into reducing lung bacterial load.

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Loss of heart myocardium is considered to be an irreversible process which can eventually lead to heart failure. Adult cardiomyocytes divide at a rate of less than 1% per year and no cardiac stem or progenitor cell type contribute significantly to the replacement of lost myocytes. One approach being pursued to replace lost heart muscle and regenerate the heart is the use of stem cell-derived cardiomyocytes.

In this publication, we focus on an in-depth review of the use of human pluripotent stem-cell derived cardiomyocytes in heart regeneration including:

• a background to cardiac regeneration and the approaches used to address this
• preclinical research and achievements in the use of cell therapy and stem cell-derived cardiomyocytes for the replacement of lost heart muscle 
• an overview of existing open questions such as how the technology works, the duration of effect, patient selection, immunological issues and how to reduce risk
• a summary of the clinical trials currently ongoing in this field

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