siRNA-Based Therapies for Pulmonary Diseases

Koli, Uday; Krishnan, R.; Pofali, Prasad; Jain, Ratnesh; Dandekar, Prajakta

doi:10.1166/jbn.2014.1928

Cited by 18 publications

(10 citation statements)

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“…The lung is an accessible tissue with attractive therapeutic targets and unmet medical needs and has been the focus of several RNAi studies in recent years 7 . In humans, ALN-RSV01, an unmodified siRNA targeting the RSV nucleocapsid (N) gene, advanced to phase IIb clinical trials, where it missed its primary endpoint but nevertheless showed a clinically meaningful treatment effect 8, 9.…”

Section: Introductionmentioning

confidence: 99%

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation

Cash-Mason

Wang

et al. 2019

Molecular Therapy - Nucleic Acids

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Clinical application of siRNA-based therapeutics outside of the liver has been hindered by the inefficient delivery of siRNA effector molecules into extra-hepatic organs and cells of interest. To understand the parameters that enable RNAi activity in vivo, it is necessary to develop a systematic approach to identify which cells within a tissue are permissive to oligonucleotide internalization and activity. In the present study, we evaluate the distribution and activity within the lung of chemically stabilized siRNA to characterize cell-type tropism and structure-activity relationship. We demonstrate intratracheal delivery of fully modified siRNA for RNAi-mediated target knockdown in lung CD11c+ cells (dendritic cells, alveolar macrophages) and alveolar epithelial cells. Finally, we use an allergen-induced model of lung inflammation to demonstrate the capacity of inhaled siRNA to induce target knockdown in dendritic cells and ameliorate lung pathology.

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Section: Introductionmentioning

confidence: 99%

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation

Cash-Mason

Wang

et al. 2019

Molecular Therapy - Nucleic Acids

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“…Bacteria and viruses cause respiratory infections in the airways [25]. Antimicrobial resistance has made treatment difficult for many infectious diseases including respiratory infections and RNAi therapeutics have proven to be effective against infections [26].…”

Section: Nucleic Acid-based Therapeuticsmentioning

confidence: 99%

Advancements in Nucleic Acid Based Therapeutics against Respiratory Viral Infections

Asha

Kumar

Sanicas³

et al. 2018

JCM

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Several viruses cause pulmonary infections due to their shared tropism with cells of the respiratory tract. These respiratory problems due to viral infection become a public health concern due to rapid transmission through air/aerosols or via direct-indirect contact with infected persons. In addition, the cross-species transmission causes alterations to viral genetic makeup thereby increasing the risk of emergence of pathogens with new and more potent infectivity. With the introduction of effective nucleic acid-based technologies, post translational gene silencing (PTGS) is being increasingly used to silence viral gene targets and has shown promising approach towards management of many viral infections. Since several host factors are also utilized by these viruses during various stages of infection, silencing these host factors can also serve as promising therapeutic tool. Several nucleic acid-based technologies such as short interfering RNAs (siRNA), antisense oligonucleotides, aptamers, deoxyribozymes (DNAzymes), and ribozymes have been studied and used against management of respiratory viruses. These therapeutic nucleic acids can be efficiently delivered through the airways. Studies have also shown efficacy of gene therapy in clinical trials against respiratory syncytial virus (RSV) as well as models of respiratory diseases including severe acute respiratory syndrome (SARS), measles and influenza. In this review, we have summarized some of the recent advancements made in the area of nucleic acid based therapeutics and highlighted the emerging roles of nucleic acids in the management of some of the severe respiratory viral infections. We have also focused on the methods of their delivery and associated challenges.

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“…While the degradation by nucleases is negligible comparing to systemic administration, delivery through the airway could be hampered by physiological barriers. The mucociliary clearance action, the surface liquid that covers the airway and macrophages along different parts of the airways, limits the transport of nucleic acids to the site of action (23). The highly viscous mucus layer in the airways traps and prevents nucleic acids reaching the underlying epithelium and propelled them out with the impact of cillated cells (24).…”

Section: Physiological Barriers To Overcomementioning

confidence: 99%

Nucleic Acid-Based Therapeutics for Pulmonary Diseases

et al. 2018

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Nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. The susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. To overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. However, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. Therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. In this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. The latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed.KEY WORDS: nucleic acid; antisense oligonucleotide (ASO); short interfering RNA (siRNA); microRNA (miRNA); pulmonary diseases.

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siRNA-Based Therapies for Pulmonary Diseases

Cited by 18 publications

References 0 publications

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation

Advancements in Nucleic Acid Based Therapeutics against Respiratory Viral Infections

Nucleic Acid-Based Therapeutics for Pulmonary Diseases

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