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MIT Team Demonstrates Novel microRNA, siRNA Delivery Tech in Lung Cancer Model

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NEW YORK (GenomeWeb) – Researchers from the Massachusetts Institute of Technology this month reported new animal data showing that an endothelial cell-targeting nanoparticle can carry microRNAs and siRNAs into lung tumors and cause the cancer to regress.

The findings, which also show that the addition of chemotherapy to the small RNA treatment can further improve survival, point to the nanoparticle technology as yet another promising approach to overcoming the delivery challenge that has long hampered the development of nucleic acid medicines.

Earlier this year, the MIT group, in collaboration with Alnylam Pharmaceuticals, reported the development of 7C1 — a polymeric nanoparticle formulation composed of low-molecular-weight polyamines and lipids — as an siRNA vehicle that selectively targeted endothelial cells with very high efficiency.

In that paper, siRNA-loaded 7C1 nanoparticles were able to transfect endothelial cells in various animal models — including ones of vascular permeability, emphysema, lung tumor growth, and lung metastasis — at low doses, without significantly reducing gene expression in hepatocytes, peritoneal immune cells, pulmonary epithelial cells, or pulmonary immune cells. The team also showed that 7C1 could be used to carry multiple different siRNAs, enabling the simultaneous knockdown of several different genes.

Notably, the nanoparticles, which are exclusively owned by MIT, proved well tolerated in animal models at doses far higher than those required for robust RNAi-mediated gene silencing.

In light of 7C1's ability to penetrate the lung endothelium while avoiding other cell types, the MIT investigators, led by Daniel Anderson and Tyler Jacks, speculated that the nanoparticle may also be effective in delivering therapeutic RNA to lung cancer cells.

In their experiments, the scientists focused on lung adenocarcinoma, the most common subtype of non-small cell lung cancer and one that is associated with frequent mutations in the oncogene KRAS and the tumor-suppressor gene p53.

"Targeted inhibition of KRAS expression and stimulation of [p53] effector functions are attractive therapeutic strategies for this disease," the researchers wrote in their paper, which appeared in the Proceedings of the National Academy of Sciences.

"However, direct and specific KRAS inhibition by small-molecule compounds has been elusive," and loss-of-function mutations in p53 continue to be a challenging therapeutic target, they noted.

In recent years, there has been increasing interest in using RNAi to target KRAS, and at least one company, Israel's Silenseed, is testing the gene-silencing technology as a cancer therapeutic in clinical trials.

Meanwhile, the miR-34 family has been found to mediate keys aspects of the p53 response, with member miR-34a also responsible for the repression of numerous oncogenes involved in cancer cell viability, cancer stemness, metastasis, and chemoresistance. Another company, Mirna Therapeutics, is currently examining a miR-34a mimic in humans for liver cancer.

As such, the MIT group sought to see whether 7C1 could effectively deliver these therapeutic payloads, beginning in vitro and then moving into a mouse model of lung adenocarcinoma.

The researchers first tested a 7C1-formulated miR-34a mimic, intravenously injecting single, 1.5 mg/kg doses of the compound into mice with established lung tumors. Levels of the miRNA were found to increase in tumors isolated from the animals, while levels of established miR-34a targets were suppressed.

Next, the team tested the effect of their drug on tumor development, giving tumor-bearing mice either saline, nanoparticles carrying a fluorescent reporter, or nanoparticles with the miR-34a payload at a dose of 1.5 mg/kg once a week for four weeks.

Treatment resulted in significantly delayed tumor progression and reduced levels of cellular proliferation compared with animals receiving control or reporter injections. Further, animals treated with the miR-34a mimic showed negligible weight loss over the treatment period despite increased expression of the miRNA in normal lung tissue, as well, suggesting that "delivery of exogenous miR-34a can suppress lung tumor development in an aggressively growing autochthonous solid tumor model," the study's authors wrote in PNAS.

Turning their attention to RNAi, the MIT investigators then twice dosed tumor-bearing mice with KRAS-targeting siRNAs loaded into 7C1 nanoparticles at 2 mg/kg, and confirmed that treatment led to a 63 percent reduction in KRAS expression compared with controls. Then, they injected 1.5 mg/kg doses of their drug into mice with established tumors once every other day for four doses, finding that tumor growth was significantly inhibited as a result.

Hypothesizing that blocking KRAS while stimulating p53 may have significant anti-tumor effects, the researchers then formulated 7C1 nanoparticles to carry both their siRNAs and miRNA mimics in equal ratios.

Mice in which tumors had been initiated 10 weeks earlier were then given either the miRNAs or siRNAs alone, or a combination of the two in doses of 2 mg/kg every other day four times. All animals tolerated the treatments well, and the combination of miRNA and RNAi therapies shrunk tumors by an average of 63 percent after two weeks.

When the chemotherapeutic cisplatin was added to the combo therapy, those mice survived significantly longer than the others that received either cisplatin or the miRNA/siRNA treatment alone.

Overall, the data demonstrate the "feasibility of small RNA-based combination therapy in a physiologically relevant mouse model of human lung cancer," the study's authors concluded. "The effective delivery of small RNAs to solid tumors in the model, combined with the modulation of divergent aspects of tumor biology as well as potent therapeutic responses, provides a compelling case for the use of small RNA therapies in human patients with lung cancer."

Still, they cautioned that because of the 7C1 nanoparticles' endothelial cell-targeting capabilities, further studies are required to determine the exact impact of delivering KRAS siRNAs and miR-34a mimics to normal tissue and the tumor microenvironment.

Anderson told Gene Silencing News that 7C1 may also prove useful with therapeutic nucleic acid cargo other than siRNAs and miRNA mimics such as antisense oligos and messenger RNA.

He said discussions are currently underway with undisclosed industry players about collaborating on the clinical development of 7C1, although he said that establishing a new company to take the technology forward is also an option.

Notably, Anderson has recently co-founded two companies — CRISPR Therapeutics, which is developing drugs based on the CRISPR/Cas 9 gene-editing technology, and Preceres, which is developing dsRNA delivery techniques for agricultural applications.

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