mRNA-Based Therapy for Lung Diseases
mRNA-based protein supplementation therapy has been encouraged to tackle various genetic lung diseases due to the advancements of the in vivo lung delivery of mRNA complexed with various vectors. Here, we give an overview of advancements in mRNA-based protein replacement therapy in lung diseases, hoping to promote the development and research of mRNA-based therapy. Creative Biogene is your reliable and professional partner in mRNA research areas. We are offering a wide series of mRNA research services, including mRNA design, synthesis, purification of mRNA, and mRNA quality control services. We continuously challenge ourselves and strive to offer our customers the finest service.
mRNA-based protein supplementation therapy to target lung diseases
SP-B deficiency, including interstitial lung disease (ILD) and acute respiratory distress syndrome (ARDS), is a rare genetic disease that causes neonatal lethality. Hydrophobic SP-B plays a crucial role in the breathing transition of neonates at birth. It helps in reducing the surface tension of the alveolus by combining dipalmitoylphosphatidylcholine (DPPC, the principal surface tension-reducing component) to form a stable surfactant film. It is reported that selective loss of SP-B causes adult respiratory failure. Given that SP-B deficiency is a monogenetic disorder, it is a perfect model for mRNA-based therapy. A study has demonstrated that modified SP-B mRNA to lung can improve SP-B expression and lung function, and a significant increase in SP-B-knockout mouse model survival.
Asthma is a multifactorial disease that manifests as a range of symptoms, including airway obstruction, wheezing, cough, chest tightness, and breathlessness, followed by recurrent bronchitis or pneumonia. Although currently there are several therapeutic options available to control the symptoms, many drugs have significant side effects. Initiating events of asthma airway disease are around the interactions between dendritic cells (DCs) and T cells, which can promote the generation of Th2. And the overactive Th2 response can induce the generation of cytokines and chemokines, followed by a cascade of immune-activating events, and finally leading to characteristics of asthma. By modulating Treg, Th2, and Th17 responses, chemically modified Foxp3 mRNA has shown a protective role in the lung of an asthma mouse model. In addition, several studies have indicated protective effects of Toll-like receptor (TLR) activation, involving Tlr1, Tlr2, and Tlr6. Researchers had found that either Tlr1/2 mRNA or Tlr2/6 mRNA led to better lung function as well as reduced airway inflammation in vivo. Besides, customized mRNA therapy provides an attractive therapeutic tool for the treatment of a patient's individual asthma phenotype.
CF is the most common life-limiting autosomal-recessive disease in the Caucasian population. It is caused by mutations in the CFTR gene. As a small conductance ATP and cyclic AMP (cAMP)-dependent chloride channel, CFTR protein can be found in the lung epithelium, including goblet cells, ciliated, and ionocytes. The presence of CFTR in these cells ensures the secretion of chloride ions, promoting hydration and mucus clearance in the airway. Protein replacement therapy with mRNA holds great potential for curing the underlying defect of CF, irrespective of their CFTR mutation status. Studies have observed a significant improvement in CFTR protein expression in vitro and in vivo (CFTR-knockout mice) by administering chemically modified human CFTR (hCFTR) mRNAs. Besides, it is also observed that a significant improvement of airway compliance and resistance after treatment with chemically modified hCFTR mRNAs.
In vivo lung delivery of mRNA complexed with vectors
mRNA holds the potential as a promising therapeutic in various genetic lung diseases. At present, the biggest obstacle of this therapy is finding safe and efficient ways to deliver mRNA molecules to the target cells. A series of biomaterials, lipids, polymers, and combined formulations, have been developed for pulmonary delivery of mRNA. Among them, polyethylenimine (PEI), hyperbranched poly (β-amino esters) are promising candidates. However, PEI can't break down easily, thus the polymer could accumulate and cause side effects with the repeated dosing. β-amino esters, a type of positively charged polymers, unlike PEI, are biodegradable. In addition to the intravenous application of mRNAs, since breathing can be used as a simple but effective delivery route to the lungs, researchers have designed an inhalable form of mRNA complexed with nanoparticles.
Fig1. Deposition of nanoparticles for delivery in the lung after intratracheal or intravenous administration. (Sahu, I., et al., 2019).
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- Sahu, I., et al. (2019). "Recent developments in mRNA-based protein supplementation therapy to target lung diseases." Molecular Therapy, 27(4), 803-823.