In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary-Based Alpha-1-Antitrypsin Deficiency Treatment

Guan, Shan; Darmstädter, Max; Xu, Chuanfei; Rosenecker, Joseph

doi:10.3390/pharmaceutics13081281

Cited by 10 publications

(3 citation statements)

References 52 publications

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“…Ease of epithelial cell targeting is a primary advantage of inhaled delivery strategies ( 31 ). Protein replacement therapy by mRNA delivery to epithelial cells is therapeutically relevant for diseases such as CF ( 51 , 52 ), asthma ( 53 ), surfactant B protein deficiency ( 54 ), and alpha-1-antitrypsin deficiency ( 55 ). Our epithelial transfection rate of greater than 20% after a single dose suggests that protein expression will be therapeutically relevant; prior research has shown that, for disease mitigation, only a fraction of lung cells in CF need to express CFTR.…”

Section: Discussionmentioning

confidence: 99%

Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination

et al. 2023

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An inhalable platform for messenger RNA (mRNA) therapeutics would enable minimally invasive and lung-targeted delivery for a host of pulmonary diseases. Development of lung-targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here, we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine- co -ester) (PACE) polyplexes for mRNA delivery using end-group modifications and polyethylene glycol. These polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for severe acute respiratory syndrome coronavirus 2 and found that intranasal vaccination with spike protein–encoding mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected susceptible mice from lethal viral challenge. Together, these results demonstrate the translational potential of PACE polyplexes for therapeutic delivery of mRNA to the lungs.

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Section: Discussionmentioning

confidence: 99%

Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination

et al. 2023

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“…As mRNA therapy production increases up, more cost-effective GMP source materials may become available [273]. GMP mRNA production begins with DNA template synthesis and continues with enzymatic IVT [274]; this is the same multistep approach used for research-scale synthesis, with extra tests to assure safety and potency [274]. Depending on the mRNA construct and chemistry involved, this process may need small alterations for changing nucleosides, capping techniques, or the removal of a template [275].…”

Section: Therapeutic Considerations and Challengesmentioning

confidence: 99%

The use of RNA-based treatments in the field of cancer immunotherapy

Chehelgerdi

2023

Mol Cancer

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Over the past several decades, mRNA vaccines have evolved from a theoretical concept to a clinical reality. These vaccines offer several advantages over traditional vaccine techniques, including their high potency, rapid development, low-cost manufacturing, and safe administration. However, until recently, concerns over the instability and inefficient distribution of mRNA in vivo have limited their utility. Fortunately, recent technological advancements have mostly resolved these concerns, resulting in the development of numerous mRNA vaccination platforms for infectious diseases and various types of cancer. These platforms have shown promising outcomes in both animal models and humans. This study highlights the potential of mRNA vaccines as a promising alternative approach to conventional vaccine techniques and cancer treatment. This review article aims to provide a thorough and detailed examination of mRNA vaccines, including their mechanisms of action and potential applications in cancer immunotherapy. Additionally, the article will analyze the current state of mRNA vaccine technology and highlight future directions for the development and implementation of this promising vaccine platform as a mainstream therapeutic option. The review will also discuss potential challenges and limitations of mRNA vaccines, such as their stability and in vivo distribution, and suggest ways to overcome these issues. By providing a comprehensive overview and critical analysis of mRNA vaccines, this review aims to contribute to the advancement of this innovative approach to cancer treatment.

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“…Not only do nebulized formulations tend to be more evenly distributed throughout the respiratory tract, but the inhalation of aerosolized vaccine is also highly acceptable and tolerable for the recipient [210]. Unfortunately, nebulization of nucleic acid-based formulations tends to be inefficient [211]. A previous study found that as little as 10% of the nucleic acid payload in a nebulization device chamber could be successfully emitted [212].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Nanotechnologies in Delivery of DNA and mRNA Vaccines to the Nasal and Pulmonary Mucosa

Tang

Cai

et al. 2022

Nanomaterials

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Recent advancements in the field of in vitro transcribed mRNA (IVT-mRNA) vaccination have attracted considerable attention to such vaccination as a cutting-edge technique against infectious diseases including COVID-19 caused by SARS-CoV-2. While numerous pathogens infect the host through the respiratory mucosa, conventional parenterally administered vaccines are unable to induce protective immunity at mucosal surfaces. Mucosal immunization enables the induction of both mucosal and systemic immunity, efficiently removing pathogens from the mucosa before an infection occurs. Although respiratory mucosal vaccination is highly appealing, successful nasal or pulmonary delivery of nucleic acid-based vaccines is challenging because of several physical and biological barriers at the airway mucosal site, such as a variety of protective enzymes and mucociliary clearance, which remove exogenously inhaled substances. Hence, advanced nanotechnologies enabling delivery of DNA and IVT-mRNA to the nasal and pulmonary mucosa are urgently needed. Ideal nanocarriers for nucleic acid vaccines should be able to efficiently load and protect genetic payloads, overcome physical and biological barriers at the airway mucosal site, facilitate transfection in targeted epithelial or antigen-presenting cells, and incorporate adjuvants. In this review, we discuss recent developments in nucleic acid delivery systems that target airway mucosa for vaccination purposes.

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In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary-Based Alpha-1-Antitrypsin Deficiency Treatment

Cited by 10 publications

References 52 publications

Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination

Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination

The use of RNA-based treatments in the field of cancer immunotherapy

Nanotechnologies in Delivery of DNA and mRNA Vaccines to the Nasal and Pulmonary Mucosa

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