Pulmonary Fibrosis-linked Genes Targeted by Specific Nanoparticles

Researchers recently developed new nanoparticles more efficient at delivering in vivo (living) RNA interference (RNAi) for silencing pulmonary fibrosis-associated genes. The study entitled “Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis” was published in the Journal of Biological Chemistry.

RNAi, a natural process that cells use to “turn off” or silence unwanted or harmful genes, has a method to regulate the expression of specific target genes, both in vitro (lab settings) and in vivo. But there are still adverse factors that restrict both RNAi technology effectiveness and safety as a therapeutic application, including being easily degraded in circulation and inside cells, and the nonspecific triggering of the innate immune system.

Attempting to overcome these limitations and to achieve optimal in vivo siRNA delivery and specific silencing, a group of researchers developed specific nanoparticles called self-assembled micelle inhibitory RNA (SAMiRNA). These particles are made from conjugating a polymer and lipid at the end of the sense strand siRNA followed by a characterization of the new particles stability, immune stimulatory function, and in vivo silencing efficacy.

Researchers observed that SAMiRNAs originated highly stable nanoparticles without signs of significant degradation throughout a whole year. Moreover, researchers tested a potential nonspecific immune stimulatory activity of SAMiRNAs by incubating them overnight with mouse peripheral blood mononuclear cells (PBMC, or blood lymphocytes, monocytes, or macrophages, all key cells of the immune system), and observed no significant immune response activation. This was denoted by a lack of expression of several immune cytokines, including tumor necrosis factor alpha (TNFalpha), interleukin 12 (IL-12) or interleukin 6 (IL-6), when compared to control particles (liposomes), which had a significant induction on the expression of these cytokines.

The results suggested that SAMiRNA particles overcome limitations linked to RNAi technology. However, its delivery and efficacy needed to be tested in vivo. To this end, the research team evaluated in vivo silencing efficacy of SAMiRNAs in mouse models of pulmonary fibrosis. More specifically, researchers used SAMiRNAs targeting the genes amphiregulin (AR) and connective tissue growth factor (CTGF) in transgenic mice with induced pulmonary fibrosis.

Researchers found that only two to three administrations of AR or CTGF SAMiRNAs was sufficient to significantly reduce the accumulation of collagen in mice lungs (fibrosis), while promoting restoration of lung function.

In their conclusion, researchers described a new type of nanoparticles that are highly efficient in in vivo delivery of stable siRNAs targeting key genes involved in pulmonary fibrosis pathogenesis. These nanoparticles may open new avenues for the treatment of the condition.