Safety and long‐term efficacy of AAV1.SERCA2a using nebulizer delivery in a pig model of pulmonary hypertension

Watanabe, Shin; Ishikawa, Kiyotake; Plataki, Maria; Bikou, Olympia; Kohlbrenner, Erik; Agüero, J.; Hadri, Lahouaria; Zarragoikoetxea, Iratxe; Fish, Kenneth; Leopold, Jane A.; Hajjar, Roger J.

doi:10.1177/2045894018799738

Cited by 17 publications

(16 citation statements)

References 7 publications

(13 reference statements)

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“…In a prevention protocol, AAV1.SERCA2a delivery attenuated adverse hemodynamic profiles as well as indices of pulmonary and cardiac remodeling in comparison with rats administered with AAV1 carrying β-galactosidase or saline. More recently, safety and long-term efficacy of AAV1.SERCA2a using nebulizer delivery has been examined in a Yukatan miniature swine model of chronic pulmonary hypertension ( Watanabe et al, 2018 ). Similar to Yorkshire pigs, Yukatan miniature swine developed PH two months after the pulmonary vein banding surgery, as demonstrated by elevated pulmonary pressures, increased vascular resistance, and RV failure.…”

Section: Emerging Therapiesmentioning

confidence: 99%

“…Similar to Yorkshire pigs, Yukatan miniature swine developed PH two months after the pulmonary vein banding surgery, as demonstrated by elevated pulmonary pressures, increased vascular resistance, and RV failure. The authors assessed the therapeutic efficacy of nebulized AAV1.SERCA2a at two months after delivery and found that nebulized AAV1.SERCA2a gene therapy significantly decreased pulmonary vascular medial thickness, pulmonary vascular resistance, and increased long-term survival compared to control animals ( Watanabe et al, 2018 ).…”

Section: Emerging Therapiesmentioning

confidence: 99%

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Current and emerging therapeutic approaches to pulmonary hypertension

Bisserier

Pradhan

Hadri

2020

Reviews in Cardiovascular Medicine

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Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.

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Section: Emerging Therapiesmentioning

confidence: 99%

Section: Emerging Therapiesmentioning

confidence: 99%

Current and emerging therapeutic approaches to pulmonary hypertension

Bisserier

Pradhan

Hadri

2020

Reviews in Cardiovascular Medicine

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“…While the injected cells were short lived in the lungs (<24 h), the injected animals showed an immediate increase in BMPR2 in their lungs, which was thought to be exosome mediated, as well as an improvement in muscularized vessels over time [ 52 ]. Another avenue to overcome the obstacle of a neutralizing immune response would be the use of Adeno-associated virus (AAV) for gene delivery, which elicits only a neglectable immune response [ 53 , 54 ]. The use of the adenovirus for BMPR2 AAV1.SERCA2a reduced RV hypertrophy, RVSP, mPAP and vascular remodeling, thereby overall reducing experimental PH [ 55 ].…”

Section: Therapeutic Strategies To Modify Bmpr2 Signalingmentioning

confidence: 99%

Novel Advances in Modifying BMPR2 Signaling in PAH

Prosseda

Ali

Spiekerkoetter

2020

Genes

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Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary arteries, that is characterized by progressive narrowing of the pulmonary arterial lumen and increased pulmonary vascular resistance, ultimately leading to right ventricular dysfunction, heart failure and premature death. Current treatments mainly target pulmonary vasodilation and leave the progressive vascular remodeling unchecked resulting in persistent high morbidity and mortality in PAH even with treatment. Therefore, novel therapeutic strategies are urgently needed. Loss of function mutations of the Bone Morphogenetic Protein Receptor 2 (BMPR2) are the most common genetic factor in hereditary forms of PAH, suggesting that the BMPR2 pathway is fundamentally important in the pathogenesis. Dysfunctional BMPR2 signaling recapitulates the cellular abnormalities in PAH as well as the pathobiology in experimental pulmonary hypertension (PH). Approaches to restore BMPR2 signaling by increasing the expression of BMPR2 or its downstream signaling targets are currently actively explored as novel ways to prevent and improve experimental PH as well as PAH in patients. Here, we summarize existing as well as novel potential treatment strategies for PAH that activate the BMPR2 receptor pharmaceutically or genetically, increase the receptor availability at the cell surface, or reconstitute downstream BMPR2 signaling.

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“…5 , 8 The Optineb® nebulizer device that is used with PH treatment inhaled pharmaceutical product Tyvaso® is an ultrasonic nebulizer device. 6 In the paper by Hajjar et al., 9 the authors investigated the safety and efficacy of nebulized gene delivery.…”

mentioning

confidence: 99%

“…Promising results were reported. 9 Pulmonary vascular resistance was lowered and long-term survival was increased. Imaging showed the distribution of the aerosol in the lungs.…”

mentioning

confidence: 99%

Inhaled medical aerosols by nebulizer delivery in pulmonary hypertension

Mansour

2018

Pulm. circ.

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Safety and long‐term efficacy of AAV1.SERCA2a using nebulizer delivery in a pig model of pulmonary hypertension

Cited by 17 publications

References 7 publications

Current and emerging therapeutic approaches to pulmonary hypertension

Current and emerging therapeutic approaches to pulmonary hypertension

Novel Advances in Modifying BMPR2 Signaling in PAH

Inhaled medical aerosols by nebulizer delivery in pulmonary hypertension

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