iPSC-CL for Congenital Heart Disease
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: HeartWorks, Inc.
Must not be taking: Amiodarone
Disqualifiers: Coronary artery disease, Cancer, Obesity, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to test the safety of lab-grown heart cells made from stem cells in subjects with congenital heart disease. The main questions it aims to answer are:
* Is this product safe to deliver to humans
* Is the conduct of this trial feasible
Participants will be asked to:
* Agree to testing and monitoring before and after product administration
* Receive investigational product
* Agree to lifelong follow-up Researchers will compare subjects from the same pool to see if there is a difference between treated and untreated subjects.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that all guideline-directed therapy should be maximized for at least 3 months before enrollment, which suggests you may need to continue your current treatments.
What data supports the effectiveness of the treatment iPSC-CL for Congenital Heart Disease?
Research shows that human induced pluripotent stem cells (hiPSCs) can be used to model heart development and congenital heart disease, helping scientists understand the disease and explore new therapies. hiPSCs have been successfully differentiated into heart cells, which can be used to study and potentially treat heart conditions.
12345Is iPSC-CL safe for use in humans?
The safety of iPSC-CL (induced pluripotent stem cells of cardiac lineage) in humans is still being studied. Research has focused on using these cells to model heart diseases and test drugs, but improving their safety for future therapies is a key challenge that needs to be addressed.
12678How is the iPSC-CL treatment different from other treatments for congenital heart disease?
The iPSC-CL treatment is unique because it uses a patient's own cells, reprogrammed into stem cells that can become heart cells, to potentially repair heart defects. This personalized approach is different from traditional treatments, which often involve surgery or medication, and it offers a novel way to address the underlying causes of congenital heart disease.
123910Eligibility Criteria
This trial is for adults aged 18-40 with single ventricle congenital heart disease, class IV heart failure, and an ejection fraction below 40%. They must have maximized all treatments, be ineligible or waiting for a heart transplant, possibly on mechanical support, and able to consent. Exclusions include substance abuse, active infections, uncontrolled depression or other conditions that could risk safety or compliance.Inclusion Criteria
I understand the study and can give my consent.
I have a heart condition where I was born with only one ventricle.
I am on the US heart transplant list but may not receive a heart in time.
+7 more
Exclusion Criteria
You are currently struggling with alcohol or drug abuse, which could prevent you from getting a heart transplant.
I have had cancer in the past.
Past or current medical problems or findings from physical examination or laboratory testing that may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality of the data obtained from the study
+23 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive one dose of Investigational Product with dose levels escalating based on treatment date
1 day
1 visit (in-person)
Short-term Follow-up
Participants are monitored for short-term safety, defined as the rate of new or worsening serious adverse events within 3 months of iPSC-CL delivery
3 months
Long-term Follow-up
Participants are monitored for long-term safety and changes in various biomarkers, with assessments up to 15 years
15 years
Participant Groups
The trial tests the safety of lab-grown heart cells (iPSC-CL) in those with congenital heart disease. Participants will receive these cells and undergo monitoring before and after treatment to assess safety and feasibility. The study includes lifelong follow-up comparing treated subjects against untreated ones from the same pool.
2Treatment groups
Experimental Treatment
Active Control
Group I: TreatedExperimental Treatment1 Intervention
Subjects in Treated arm will receive one dose of Investigational Product. Within this arm are three dose levels. Dose level selection will be determined by product availability subjects have available product and when they can be treated. Dose levels will escalate in order of treatment date.
Group II: ControlActive Control1 Intervention
Subjects who enroll but do not receive Investigational Product will be placed in the control arm.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo ClinicRochester, MN
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Who Is Running the Clinical Trial?
HeartWorks, Inc.Lead Sponsor
References
Translational potential of hiPSCs in predictive modeling of heart development and disease. [2023]Congenital heart disease (CHD) represents a major class of birth defects worldwide and is associated with cardiac malformations that often require surgical intervention immediately after birth. Despite the intense efforts from multicentric genome/exome sequencing studies that have identified several genetic variants, the etiology of CHD remains diverse and often unknown. Genetically modified animal models with candidate gene deficiencies continue to provide novel molecular insights that are responsible for fetal cardiac development. However, the past decade has seen remarkable advances in the field of human induced pluripotent stem cell (hiPSC)-based disease modeling approaches to better understand the development of CHD and discover novel preventative therapies. The iPSCs are derived from reprogramming of differentiated somatic cells to an embryonic-like pluripotent state via overexpression of key transcription factors. In this review, we describe how differentiation of hiPSCs to specialized cardiac cellular identities facilitates our understanding of the development and pathogenesis of CHD subtypes. We summarize the molecular and functional characterization of hiPSC-derived differentiated cells in support of normal cardiogenesis, those that go awry in CHD and other heart diseases. We illustrate how stem cell-based disease modeling enables scientists to dissect the molecular mechanisms of cell-cell interactions underlying CHD. We highlight the current state of hiPSC-based studies that are in the verge of translating into clinical trials. We also address limitations including hiPSC-model reproducibility and scalability and differentiation methods leading to cellular heterogeneity. Last, we provide future perspective on exploiting the potential of hiPSC technology as a predictive model for patient-specific CHD, screening pharmaceuticals, and provide a source for cell-based personalized medicine. In combination with existing clinical and animal model studies, data obtained from hiPSCs will yield further understanding of oligogenic, gene-environment interaction, pathophysiology, and management for CHD and other genetic cardiac disorders.
Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as a Model for Heart Development and Congenital Heart Disease. [2022]Congenital heart disease (CHD) remains a significant health problem, with a growing population of survivors with chronic disease. Despite intense efforts to understand the genetic basis of CHD in humans, the etiology of most CHD is unknown. Furthermore, new models of CHD are required to better understand the development of CHD and to explore novel therapies for this patient population. In this review, we highlight the role that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes can serve to enhance our understanding of the development, pathophysiology and potential therapeutic targets for CHD. We highlight the use of hiPSC-derived cardiomyocytes to model gene regulatory interactions, cell-cell interactions and tissue interactions contributing to CHD. We further emphasize the importance of using hiPSC-derived cardiomyocytes as personalized research models. The use of hiPSCs presents an unprecedented opportunity to generate disease-specific cellular models, investigate the underlying molecular mechanisms of disease and uncover new therapeutic targets for CHD.
Induced Pluripotent Stem Cells 10 Years Later: For Cardiac Applications. [2022]Induced pluripotent stem cells (iPSCs) are reprogrammed cells that have features similar to embryonic stem cells, such as the capacity of self-renewal and differentiation into many types of cells, including cardiac myocytes. Although initially the reprogramming efficiency was low, several improvements in reprogramming methods have achieved robust and efficient generation of iPSCs without genomic insertion of transgenes. iPSCs display clonal variations in epigenetic and genomic profiles and cellular behavior in differentiation. iPSC-derived cardiac myocytes (iPSC cardiac myocytes) recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models, and are useful for drug discovery and toxicology testing. In addition, iPSC cardiac myocytes can help with patient stratification in regard to drug responsiveness. Furthermore, they can be used as source cells for cardiac regeneration in animal models. Here, we review recent progress in iPSC technology and its applications to cardiac diseases.
Selection via pluripotency-related transcriptional screen minimizes the influence of somatic origin on iPSC differentiation propensity. [2022]The value of induced pluripotent stem cells (iPSCs) within regenerative medicine is contingent on predictable and consistent iPSC differentiation. However, residual influence of the somatic origin or reprogramming technique may variegate differentiation propensity and confound comparative genotype/phenotype analyses. The objective of this study was to define quality control measures to select iPSC clones that minimize the influence of somatic origin on differentiation propensity independent of the reprogramming strategy. More than 60 murine iPSC lines were derived from different fibroblast origins (embryonic, cardiac, and tail tip) via lentiviral integration and doxycycline-induced transgene expression. Despite apparent equivalency according to established iPSC histologic and cytomorphologic criteria, clustering of clonal variability in pluripotency-related gene expression identified transcriptional outliers that highlighted cell lines with unpredictable cardiogenic propensity. Following selection according to a standardized gene expression profile calibrated by embryonic stem cells, the influence of somatic origin on iPSC methylation and transcriptional patterns was negated. Furthermore, doxycycline-induced iPSCs consistently demonstrated earlier differentiation than lentiviral-reprogrammed lines using contractile cardiac tissue as a measure of functional differentiation. Moreover, delayed cardiac differentiation was predominately associated with upregulation in pluripotency-related gene expression upon differentiation. Starting from a standardized pool of iPSCs, relative expression levels of two pluripotency genes, Oct4 and Zfp42, statistically correlated with enhanced cardiogenicity independent of somatic origin or reprogramming strategy (R(2) = 0.85). These studies demonstrate that predictable iPSC differentiation is independent of somatic origin with standardized gene expression selection criteria, while the residual impact of reprogramming strategy greatly influences predictable output of tissue-specification required for comparative genotype/phenotype analyses.
Thymic derived iPs cells can be differentiated into cardiomyocytes. [2022]Ventricular septal defect (VSD) is one of the common congenital heart malformations. Several factors lead to the development of VSD, including familial causes, exposure to certain drugs, infectious agents, and maternal metabolic disturbances. We considered that induced pluripotent stem (iPS) cells derived from VSD patients can be used to study the origin and pathogenesis of the VSD. Here, we show generation and cardiomyocyte differentiation potential of iPS cells from thymic epithelial cells of a patient with VSD (TECs-VSD) by overexpressing the four factors: OCT4, SOX2, NANOG, and LIN28 with lentiviral vectors. The self-renewal and pluripotency of the VSD-iPS cells was verified in iPS cells by in vitro expression of pluripotency markers and formation of teratoma in vivo. iPS cell lines from VSD patients differentiated into functional cardiomyocytes can serve as a model system for studying the pathophysiology and identifying etiology of VSD.
Stem cells in pediatric cardiology. [2021]The ability to reprogram virtually any cell of human origin to behave like embryonic or pluripotent stem cells is a major breakthrough in stem cell biology. Human induced pluripotent stem cells (iPSC) provide a unique opportunity to study "disease in a dish" within a defined genetic and environmental background. Patient-derived iPSCs have been successfully used to model cardiomyopathies, rhythm disorders and vascular disorders. They also provide an exciting opportunity for drug discovery and drug repurposing for disorders with a known molecular basis including childhood onset heart disease, particularly cardiac genetic disorders. The review will discuss their use in drug discovery, efficacy and toxicity studies with emphasis on challenges in pediatric-focused drug discovery. Issues that will need to be addressed in the coming years include development of maturation protocols for iPSC-derived cardiac lineages, use of iPSCs to study not just cardiac but extra-cardiac phenotypes in the same patient, scaling up of stem cell platforms for high-throughput drug screens, translating drug testing results to clinical applications in the paradigm of personalized medicine, and improving both the efficiency and the safety of iPSC-derived lineages for future stem cell therapies.
Chronic drug-induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell-derived cardiomyocytes. [2022]In the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity.
Generation and characterization of a human induced pluripotent stem cell (iPSC) line from a patient with congenital heart disease (CHD). [2023]Epstein-Barr virus (EBV) immortalized lymphoblastoid cell lines (LCLs) are widely used for banking. This bioresource could be leveraged for creating human iPSC lines to model diseases including CHD. We generated an LCL-derived iPSC line (NCHi001-A) from a patient with congenital aortic valve stenosis. NCHi001-A was EBV and transgenes free, exhibited stem cell-like morphology, expressed pluripotency markers, has a normal karyotype, and could be differentiated into cells of three germ layers in vitro. Relationship inference via a microarray-based analysis showed NCHi001-A is identical to the parental cell line. NCHi001-A can be used for disease modeling, drug discovery, and cell therapy development.
Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases. [2023]Congenital heart disease includes a wide variety of structural cardiac defects, the most severe of which are single ventricle defects (SVD). These patients suffer from significant morbidity and mortality; however, our understanding of the developmental etiology of these conditions is limited. Model organisms offer a window into normal and abnormal cardiogenesis yet often fail to recapitulate complex congenital heart defects seen in patients. The use of induced pluripotent stem cells (iPSCs) derived from patients with single-ventricle defects opens the door to studying SVD in patient-derived cardiomyocytes (iPSC-CMs) in a variety of different contexts, including organoids and chamber-specific cardiomyocytes. As the genetic and cellular causes of SVD are not well defined, patient-derived iPSC-CMs hold promise for uncovering mechanisms of disease development and serve as a platform for testing therapies. The purpose of this review is to highlight recent advances in iPSC-based models of SVD.
Generating patient-specific induced pluripotent stem cells-derived cardiomyocytes for the treatment of cardiac diseases. [2018]Induced pluripotent stem cells (iPSC) represent an appealing cell source to develop disease-modeling assays, drug testing assays and cell-based replacement therapies especially for cardiac disorders.