Genetic Delivery and Gene Therapy in Pulmonary Hypertension

Rai, Nabham; Shihan, Mazen; Seeger, Werner; Schermuly, Ralph T.; Novoyatleva, Tatyana

doi:10.3390/ijms22031179

Cited by 22 publications

(15 citation statements)

References 328 publications

(214 reference statements)

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“…In the past years, several groups have explored gene therapy as a strategy to improve or correct PAH in different models. Targets of interest that have been studied include several of genes and viral vectors [35]. It should be noted that in recent years that AAV vector has gained popularity in translational medicine [36,37].…”

Section: Discussionmentioning

confidence: 99%

Acid Ceramidase Gene Therapy Ameliorates Pulmonary Arterial Hypertension with Right Heart Dysfunction

Katz

Hadas

Vincek

et al. 2022

Preprint

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BackgroundUp-regulation of ceramides in pulmonary arterial hypertension (PAH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PAH model.MethodsA model of PAH was created by the combination of pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PAH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery.ResultsHemodynamic assessment four weeks after PAH model creation demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p < 0.001), which was consistent with the definition of PAH. We documented a significant increase in pulmonary vascular resistance in the saline-treated (6.79 ± 0.85 mm Hg) and empty capsid (6.94 ± 0.47 mm Hg) groups, but not in animals receiving Anc80L65.AC (4.44 ± 0.71 mm Hg, p < 0.001). Morphometric analysis demonstrated an increase in medial wall thickness in control groups in comparison to those treated with acid ceramidase. After acid ceramidase gene delivery, a significant decrease of pro-inflammatory factors, interleukins, and senescence markers was observed.ConclusionGene delivery of acid ceramidase provided tropism to pulmonary tissue and ameliorated vascular remodeling with right ventricular dysfunction in pulmonary arterial hypertension.

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Section: Discussionmentioning

confidence: 99%

Acid Ceramidase Gene Therapy Ameliorates Pulmonary Arterial Hypertension with Right Heart Dysfunction

Katz

Hadas

Vincek

et al. 2022

Preprint

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“…Gene therapies targeting the pulmonary endothelium have been identified for the treatment of genetic disorders such as alpha-1 antitrypsin deficiency (AATD) and pulmonary arterial hypertension (PAH). ,− AATD is caused by a mutation in the AAT gene that encodes a protease inhibitor that protects against inflammatory damage. While endogenous AAT is produced in the liver, transduction of pulmonary ECs with the AAT gene may offer a more direct treatment for AATD-associated illnesses that affect the lung such as emphysema. , PAH can be caused by a number of factors including loss-of-function mutations in caveolin-1 (CAV1), which acts as a scaffolding protein in caveolae membranes and regulates signaling complexes relevant to PAH including eNOS activity.…”

Section: Nucleic Acid Therapies For Endothelial Pathologiesmentioning

confidence: 99%

Nucleic Acid Delivery to the Vascular Endothelium

et al. 2022

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This Review examines the state-of-the-art in the delivery of nucleic acid therapies that are directed to the vascular endothelium. First, we review the most important homeostatic functions and properties of the vascular endothelium and summarize the nucleic acid tools that are currently available for gene therapy and nucleic acid delivery. Second, we consider the opportunities available with the endothelium as a therapeutic target and the experimental models that exist to evaluate the potential of those opportunities. Finally, we review the progress to date from investigations that are directly targeting the vascular endothelium: for vascular disease, for peri-transplant therapy, for angiogenic therapies, for pulmonary endothelial disease, and for the blood− brain barrier, ending with a summary of the future outlook in this field.

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“…Recent studies have found that Apela, also known as ELABELA/Toddler/ELA32, a new ligand of the apelin peptide jejunum (APJ) receptor, not only plays an important biological role in heart development, heart failure, and maintaining fluid balance and angiogenesis but also has an important biological effect in reducing pulmonary hypertension and improving right heart function exhaustion in a pulmonary artery rat model 5–10 . Previous studies have shown successful effects of gene therapy in pulmonary hypertension 11 . This study further explores the biological effect and potential molecular mechanism of adeno‐associated virus (AAV)‐mediated Apela gene therapy in a rat model of pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 99%

Apela gene therapy alleviates pulmonary hypertension in rats

Jin

Pan

et al. 2022

The FASEB Journal

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Pulmonary artery hypertension (PAH) is a common disease that threatens human health. At present, no treatment can cure PAH, and the prognosis is poor. Therefore, it is important to determine new targets for PAH treatment. Recently, a novel endogenous ligand Apela (ELABELA/Toddler/ELA32) of apelin peptide jejunum (APJ) receptor was identified as a possible PAH target. This study explored the potential effect of Apela gene therapy on rats with PAH. An AAV‐ELA32 recombinant expression vector was constructed by molecular cloning. Purified adeno‐associated virus (AAV) was injected into monocrotaline (MCT)‐induced PAH rats via tail vein 1 and 2 weeks after modeling. Apela gene therapy significantly reduced the increased right ventricular systolic pressure and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in PAH rats. The results of histopathology and immunofluorescence showed that Apela gene therapy not only reduced the rate of pulmonary arteriole muscularization and media thickening in PAH rats but also inhibited the endothelial‐to‐mesenchymal transition of the pulmonary arteriole. Western blotting showed that Apela gene therapy up‐regulated the expression of KLF2/eNOs and BMPRII/SMAD4 in pulmonary arterioles of PAH rats. Overall, the results show that Apela gene therapy can inhibit pulmonary arteriolar vascular remodeling and reduce pulmonary artery pressure in PAH rats. These effects may be related to KLF2/eNOs and BMPRII/SMAD4 signaling pathways. The apelinergic system may be a potential new target for the prevention and treatment of PAH.

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Genetic Delivery and Gene Therapy in Pulmonary Hypertension

Cited by 22 publications

References 328 publications

Acid Ceramidase Gene Therapy Ameliorates Pulmonary Arterial Hypertension with Right Heart Dysfunction

Acid Ceramidase Gene Therapy Ameliorates Pulmonary Arterial Hypertension with Right Heart Dysfunction

Nucleic Acid Delivery to the Vascular Endothelium

Apela gene therapy alleviates pulmonary hypertension in rats

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