Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome

Kaushal, Sunjay; Wehman, Brody; Pietris, Nicholas; Naughton, Casey; Bentzen, Søren M.; Bigham, Grace; Mishra, Rachana; Sharma, Sudhish; Deatrick, Kristopher B.; Huang, Shuqiang; Mehta, Helina; Ravekes, William; Hibino, Naru; DiFede, Darcy L.; Khan, Aisha; Hare, Joshua M.

doi:10.1016/j.ahj.2017.06.009

Cited by 41 publications

(37 citation statements)

References 25 publications

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“…The seminal ELPIS trial (Allogeneic Human MEsenchymal Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome: An Open Label Pilot Study) is being initiated to evaluate the safety and efficacy of allogeneic bone marrow derived MSCs in HLHS patients [16]. While this trial represents a significant advance for cardiac regenerative therapies for patients with congenital heart disease, the potency of stem cell therapy for cardiac disease in adults remains under scrutiny [17].…”

Section: Discussionmentioning

confidence: 99%

Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload

et al. 2019

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Right ventricle (RV) failure secondary to pressure overload is associated with a loss of myocardial capillary density and an increase in oxidative stress. We have previously found that human neonatal thymus mesenchymal stem cells (ntMSCs) promote neovascularization, but the ability of ntMSCs to express the antioxidant extracellular superoxide dismutase (SOD3) is unknown. We hypothesized that ntMSCs express and secrete SOD3 as well as improve survival in the setting of chronic pressure overload. To evaluate this hypothesis, we compared SOD3 expression in ntMSCs to donor-matched bone-derived MSCs and evaluated the effect of ntMSCs in a rat RV pressure overload model induced by pulmonary artery banding (PAB). The primary outcome was survival, and secondary measures were an echocardiographic assessment of RV size and function as well as histological studies of the RV. We found that ntMSCs expressed SOD3 to a greater degree as compared to bone-derived MSCs. In the PAB model, all ntMSC-treated animals survived to the study endpoint whereas control animals had significantly decreased survival. Treatment animals had significantly less RV fibrosis and increased RV capillary density as compared to controls. We conclude that human ntMSCs demonstrate a therapeutic effect in a model of chronic RV pressure overload, which may in part be due to their antioxidative, antifibrotic, and proangiogenic effects. Given their readily available source, human ntMSCs may be a candidate cell therapy for individuals with congenital heart disease and a pressure-overloaded RV.

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Section: Discussionmentioning

confidence: 99%

Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload

et al. 2019

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“…Clearly, biological repair and replacement of lost myocardium using h-iPSCs that can form myocardium (versus skeletal muscle) are feasible, and clinical trials to determine safety and feasibility in adult heart failure patients should occur in the near future. It is important to note that many adult stem cell trials have shown statistically and clinically significant improvements in heart failure patients, and studies using stem cells have shown encouraging results for children with congenital heart disease [1][2][3][4]. The use of isolated cells, or the exosomes extracted from cells, may represent a much simpler therapeutic product to manufacture, verify, and distribute for future clinical therapy compared to the complexities of generating engineered tissues (multi-layer cell sheets and ECTs).…”

Section: Future Directions and Clinical Implicationsmentioning

confidence: 99%

“…There are currently many cardiac "cellular therapies" undergoing preclinical and clinical trials in adults. There have been small, encouraging clinical trials using stem cells in infants with hypoplastic left heart syndrome in Japan [1][2][3] that have led to similar trials in the United States [4][5][6]. It is clear that injected or implanted cells do not survive and that functional improvement occurs via paracrine mechanisms that impact angiogenesis and/or remodeling.…”

Section: Introductionmentioning

confidence: 99%

Progress in the Generation of Multiple Lineage Human-iPSC-Derived 3D-Engineered Cardiac Tissues for Cardiac Repair

Setozaki

Kowalski

et al. 2020

Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension

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“…The ELPIS (Allogeneic Human MSC Injection in Patients With Hypoplastic Left Hearts, NCT02398604), phase I/II trial is an ongoing clinical trial that investigates the safety and feasibility of intramyocardially injected allogeneic MSCs as opposed to an autologous preparation at the time of the stage II operation in HLHS patients (Figure). 84 This trial may lay the groundwork for an off-the-shelf, MSC-based product for CHD patients…”

Section: Clinical Trials Of Stem Cell Therapy In Childrenmentioning

confidence: 99%

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

Bittle

Morales

Deatrick

et al. 2018

Circulation Research

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Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

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Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome

Cited by 41 publications

References 25 publications

Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload

Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload

Progress in the Generation of Multiple Lineage Human-iPSC-Derived 3D-Engineered Cardiac Tissues for Cardiac Repair

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

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