Targeted Delivery of Genes to Endothelial Cells and Cell‐ and Gene‐Based Therapy in Pulmonary Vascular Diseases

Suen, Colin; Mei, Shirley H. J.; Kugathasan, Lakshmi; Stewart, Duncan J.

doi:10.1002/cphy.c120034

Cited by 16 publications

(13 citation statements)

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“…Thus, an adjunctive therapy that could directly address and attenuate severe occlusive arteriopathy is greatly needed. This rationale has been the basis for studies of gene- and cell-based therapies in animal models of PAH [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Middleton

Fournier

et al. 2017

PLoS ONE

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Pulmonary arterial hypertension (PAH) is a progressive condition characterized by occlusive pulmonary arteriopathy, in which survival remains poor despite pharmacologic advances. The aim of this study was to evaluate the ability of cardiosphere-derived cells (CDCs), cardiac progenitor cells with potent anti-inflammatory and immunomodulatory properties, to attenuate hemodynamic and morphometric remodeling of the right ventricle (RV) and pulmonary arterioles in rats with established monocrotaline (MCT)-induced PAH. Animals were divided into 3 groups: 1) Control (CTL), 2) PAH in which CDCs were centrally infused (CDC) and 3) PAH in which saline was given (Sham). Significant increments in RV systolic pressure (RVSP) and RV hypertrophy were noted in Sham animals compared to CTL. In CDC rats at day 35, RSVP fell (- 38%; p< 0.001) and RV hypertrophy decreased (-26%; p< 0.01). TAPSE and cardiac output were preserved in all 3 groups at day 35. Pulmonary arteriolar wall thickness was greater in Sham rats compared to CTL, and reduced in CDC animals for vessels 20–50 μm (P<0.01; back to CTL levels) and 50–80μm (P<0.01) in diameter. The macrophage population was increased in Sham animals compared to CTL (P< 0.001), but markedly reduced in CDC rats. In conclusion, infusion of CDCs markedly attenuated several key pathophysiologic features of PAH. As adjunctive therapy to PAH-specific agents, CDCs have the potential to impact on the pathobiology of adverse pulmonary arteriolar remodeling, by acting on multiple mechanisms simultaneously.

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Section: Introductionmentioning

confidence: 99%

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Middleton

Fournier

et al. 2017

PLoS ONE

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“…Current therapeutic approaches aim to prevent further pulmonary damage by using parenteral, inhaled, and oral combinations of prostaglandins (e.g., prostanoids), endothelin receptor antagonists, diuretics, calcium channel blockers, and phosphodiesterase-5 inhibitors (19,112,134). Hopes of reversing established PAH via regenerative approaches, including the use of endothelial progenitor cells and mesenchymal stem cells, await extensive clinical testing (155). Riociguat is a soluble guanylate cyclase stimulator that belongs to a new class of vasodilators currently in clinical development, which reversed right heart hypertrophy and ventricular remodeling associated with PAH in rats and mice (5).…”

Section: Hiv-associated Challenges In the Lungmentioning

confidence: 99%

The Complexity of HIV Persistence and Pathogenesis in the Lung Under Antiretroviral Therapy: Challenges Beyond AIDS

Almodóvar

2014

Viral Immunology

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Antiretroviral therapy (ART) represents a significant milestone in the battle against AIDS. However, we continue learning about HIV and confronting challenges 30 years after its discovery. HIV has cleverly tricked both the host immune system and ART. First, the many HIV subtypes and recombinant forms have different susceptibilities to antiretroviral drugs, which may represent an issue in countries where ART is just being introduced. Second, even under the suppressive pressures of ART, HIV still increases inflammatory mediators, deregulates apoptosis and proliferation, and induces oxidative stress in the host. Third, the preference of HIV for CXCR4 as a co-receptor may also have noxious outcomes, including potential malignancies. Furthermore, HIV still replicates cryptically in anatomical reservoirs, including the lung. HIV impairs bronchoalveolar T-lymphocyte and macrophage immune responses, rendering the lung susceptible to comorbidities. In addition, HIV-infected individuals are significantly more susceptible to long-term HIV-associated complications. This review focuses on chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, and lung cancer. Almost two decades after the advent of highly active ART, we now know that HIV-infected individuals on ART live as long as the uninfected population. Fortunately, its availability is rapidly increasing in low- and middle-income countries. Nevertheless, ART is not risk-free: the developed world is facing issues with antiretroviral drug toxicity, resistance, and drug-drug interactions, while developing countries are confronting issues with immune reconstitution inflammatory syndrome. Several aspects of the complexity of HIV persistence and challenges with ART are discussed, as well as suggestions for new avenues of research.

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“…Recent understanding of the role of adult stem and progenitor cells in the maintenance of vascular homeostasis and repair of injury has stimulated interest in the potential for regenerative cell therapies for PAH. Most of the preclinical studies of cell therapy for PAH have used two cell types in particular, early-outgrowth endothelial progenitor cells (EPCs, also known as circulating angiogenic cells, myeloid angiogenic cells) and mesenchymal stromal cells (MSCs, also known as mesenchymal stem cells, adult stem cells) [ 8 , 9 ]. EPCs and MSCs have been described as dynamic and responsive cells that can migrate to sites of vascular injury in several in vivo animal disease models [ 10 ], facilitating neovascularization and reducing inflammation [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Most of the preclinical studies of cell therapy for PAH have used two cell types in particular, early-outgrowth endothelial progenitor cells (EPCs, also known as circulating angiogenic cells, myeloid angiogenic cells) and mesenchymal stromal cells (MSCs, also known as mesenchymal stem cells, adult stem cells) [ 8 , 9 ]. EPCs and MSCs have been described as dynamic and responsive cells that can migrate to sites of vascular injury in several in vivo animal disease models [ 10 ], facilitating neovascularization and reducing inflammation [ 8 ]. As a treatment for PAH, preclinical studies involving these cell types have demonstrated efficacy in improving key pathological features of PAH such as cardiopulmonary hemodynamics, restoring the degenerated microvascular area, and reducing both right ventricular and pulmonary vascular remodeling [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…EPCs and MSCs have been described as dynamic and responsive cells that can migrate to sites of vascular injury in several in vivo animal disease models [ 10 ], facilitating neovascularization and reducing inflammation [ 8 ]. As a treatment for PAH, preclinical studies involving these cell types have demonstrated efficacy in improving key pathological features of PAH such as cardiopulmonary hemodynamics, restoring the degenerated microvascular area, and reducing both right ventricular and pulmonary vascular remodeling [ 8 ]. A small number of clinical studies involving stem/progenitor cell therapy on PAH patients have been completed or are underway and show some promise in controlling the extent of the disease [ 3 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol

et al. 2016

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BackgroundPulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies.MethodsWe will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and individual study reporting will be assessed according to an itemized checklist based on the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines.DiscussionThis systematic review will examine the efficacy and safety of regenerative cell therapy in preclinical models of PAH. As well, the literature will be assessed for study quality and risk of bias. The results will guide the design of future clinical trials and preclinical animal studies.Systematic review registrationCAMARADES (http://www.dcn.ed.ac.uk/camarades/SyRF/Protocols.htm).Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-016-0265-x) contains supplementary material, which is available to authorized users.

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Targeted Delivery of Genes to Endothelial Cells and Cell‐ and Gene‐Based Therapy in Pulmonary Vascular Diseases

Cited by 16 publications

References 250 publications

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

The Complexity of HIV Persistence and Pathogenesis in the Lung Under Antiretroviral Therapy: Challenges Beyond AIDS

Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol

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