Delivery Of Stem Cell Therapies Research Articles

The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials

BackgroundDespite limited human data, there is a growing interest in the use of stem cell therapy (SCT) for erectile dysfunction (ED). AimTo determine the effect of transendocardial stem cell injection on erectile function on men with cardiomyopathy and ED. MethodsWe used International Index of Erectile Function (IIEF) scores collected from men enrolled in 3 separate randomized controlled trials: Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy (POSEIDON), Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy (TAC-HFT), and Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (TRIDENT). These trials recruited patients with ischemic cardiomyopathy and ejection fraction less than 50%. Inclusion and exclusion criteria were identical in all 3 trials. The primary intervention in these trials included transendocardial stem cell injection of stem cells or placebo via cardiac catheterization. The follow-up period was 1 year. IIEF data were collected at baseline and at multiple time points in each trial. OutcomesWe investigated erectile function over time based on cell dose, cell source (autologous vs allogenic), cell type (mesenchymal stem cells vs bone marrow mononuclear cells), and comparing men who received SCT with those who received placebo. ResultsA total of 36 men were identified with complete IIEF data. 8 men received placebo injection, and 28 received SCT. The median age was 66.5 years. Comorbidities were similar among all men. Analysis was performed on men with ED, defined by an IIEF-EF score of 24 or less. In the placebo and all-comer SCT group, the median IIEF-EF score was 5 [1–8] and 5 [1–15] at baseline and was 3.5 [3–5.8] and 7 [1–18] at 12 months (P > .05). When analyzed by cell dose, the IIEF-EF score in men who received 200 million cells increased significantly over 12 months (14 [4–23] to 20 [15–24.5], P = .014.) Similarly, an autologous cell source resulted in a similar increase from baseline to 12 months (14 [3.8–23.3] to 20 [12–22], P = .030). Clinical ImplicationsErectile function may improve after systemic delivery of SCT in men with ischemic cardiomyopathy and at least mild ED. Strengths & LimitationsThis post hoc analysis is the first to investigate the effect of SCT on erectile function using randomized, placebo-controlled data. Weaknesses include that ED was not a primary end point, and men were not originally recruited based on erectile function. ConclusionFuture trials on systemic delivery of SCT for ED should focus on high cell dose and autologous cell source, as these seem to provide the best response in men with at least mild ED.Ory J, Saltzman RG, Blachman-Braun R, et al. The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials. J Sex Med 2020;17:695–701.

Abstract 18968: Correlation Between Myocardial Perfusion and Contractility by SPECT and MRI, and Electromechanical Mapping Parameters in Patients with Advanced Coronary Artery Disease. A PRECISE Substudy

Introduction: electromechanical mapping (EMM) of the left ventricle (LV) is a new technique that provides us with voltage (unipolar and bipolar voltage) and contractility (lineal local shortening) information of the LV. The objective of this study was to assess the correlation between EMM parameters and myocardial perfusion and contractility by SPECT/MRI, in patients with advanced chronic coronary artery disease (CAD). Methods: the PRECISE clinical trial of freshly isolated adipose-derived stem cells for angiogenesis included pts with chronic stable CAD, reversible perfusion defects detectable by SPECT and not amenable for revascularization. Wall motion score index was assessed with MRI imaging in all patients (normal=1; hypokinetic=2; akinetic=3). Perfusion was studied with SPECT Tc-99m sestamibi (normal=grade 0; most impaired=grade 4) and EMM was performed with the NOGA XP system, all using the same 17-segment polar map of the LV. All studies were performed and analyzed by independent observers blinded to the results of the other techniques. Results: 27 consecutive pts were included (62±8 years and 77% male). A total of 865 SPECT and MRI segments were correlated with the corresponding EMM data. Segments with better perfusion at rest and stress (fig.1), and segments with better WMSI by MRI (fig.2) had better voltage and local shortening parameters. Conclusions: EMM is a useful technique for assessing myocardial health status in terms of perfusion and contractility in chronic CAD pts, and can be used for a precise delivery of stem cell therapy.

Stem Cell Transplantation in Cardiovascular Disease: An Update

Despite the development of novel therapeutic strategies, cardiovascular diseases remain the main cause of morbidity and mortality worldwide. Many phase 1 and 2 clinical trials have reported the safety, feasibility and promising potential of stem cell transplantation, however, the optimal cell types, timing of infusion, cell dosage and routes of administration remain to be determined. This paper reviews the findings of various clinical studies and discusses the challenges facing the delivery of stem cell therapy in cardiovascular diseases.

Design of targeted cardiovascular molecular imaging probes.

Molecular imaging relies on the development of sensitive and specific probes coupled with imaging hardware and software to provide information about the molecular status of a disease and its response to therapy, which are important aspects of disease management. As genomic and proteomic information from a variety of cardiovascular diseases becomes available, new cellular and molecular targets will provide an imaging readout of fundamental disease processes. A review of the development and application of several cardiovascular probes is presented here. Strategies for labeling cells with superparamagnetic iron oxide nanoparticles enable monitoring of the delivery of stem cell therapies. Small molecules and biologics (e.g., proteins and antibodies) with high affinity and specificity for cell surface receptors or cellular proteins as well as enzyme substrates or inhibitors may be labeled with single-photon-emitting or positron-emitting isotopes for nuclear molecular imaging applications. Labeling of bispecific antibodies with single-photon-emitting isotopes coupled with a pretargeting strategy may be used to enhance signal accumulation in small lesions. Emerging nanomaterials will provide platforms that have various sizes and structures and that may be used to develop multimeric, multimodal molecular imaging agents to probe one or more targets simultaneously. These platforms may be chemically manipulated to afford molecules with specific targeting and clearance properties. These examples of molecular imaging probes are characteristic of the multidisciplinary nature of the extraction of advanced biochemical information that will enhance diagnostic evaluation and drug development and predict clinical outcomes, fulfilling the promise of personalized medicine and improved patient care.

Stem Cell Therapy Delivery: Treading the Regulatory Tightrope

The concept of stem cell therapy has engaged the attention of the public and scientists alike. Intensive research effort is focused upon understanding the biology and therapeutic potential of embryonic and adult stem cells, with the eventual goal of treating such pathologies as Parkinson's disease, diabetes, neurological injury and degenerations and cancer. Ex vivo expansion and transplantation of limbal epithelial stem cells to the corneas to treat blinding ocular surface disease was one of the first stem cell therapies to successfully reach the clinic. However, limbal epithelial stem cell research and therapy delivery has remained largely within the noncommercial academic clinician-scientist environment from which it was originally pioneered. In our experience, gaining regulatory approval has been as great a hurdle as surmounting the scientific challenges of stem cell therapy. Based upon our model of delivering 'accredited' limbal epithelial stem cell therapy to patients in compliance with Good Manufacturing Practice and the new European Union Tissues and Cells Directive, we address the key regulatory questions. This may help colleagues who are developing innovative academic research-driven stem cell therapies regarding donor consent, raw materials, quality assurance, laboratory specification, indemnity and funding.