Skip to main content
Premium Trial:

Request an Annual Quote

Yale Team Demonstrates Tumor-targeting Approach for microRNA Inhibitors


NEW YORK (GenomeWeb) – A Yale University team has reported on a novel delivery strategy for microRNA inhibitors that selectively targets tumors while avoiding systemic clearance and enables cellular entry through a non-endocytic pathway.

The data, which appeared in Nature, provide a new model for using miRNA antagonists as cancer therapeutics that the researchers believe overcomes many of the limitations of currently approaches.

To date, miRNAs have been implicated in a number of different diseases, including many cancers. Current approaches to silencing miRNAs for therapeutic applications include antisense oligonucleotides and peptide nucleic acids (PNAs), but these strategies suffer from limitations including non-specific organ distribution, reticuloendothelial system clearance, and endolysosomal trafficking.

To address this, the Yale team aimed to exploit the acidic nature of tumors using a peptide called pHLIP — short for pH low insertion peptide — which was developed at the university several years ago. In previous studies, pHLIPs have been shown to form inducible transmembrane alpha-helices under acidic conditions and to translocate membrane-impermeable molecules into cells through a non-endocytic route. Additionally, pHLIPs have been shown to target epithelial tumors when administered systemically.

In the latest study, the Yale scientists demonstrated first that the pHLIP peptide can localize to tumors of lymphoid origin in a subcutaneous flank model and a model of disseminated lymphadenopathy while avoiding the liver.

Looking to exploit these targeting properties for the delivery of miRNA inhibitors to tumors — a long-time focus for Frank Slack, senior author of the Nature paper and a former Yale researcher — the group developed a PNA delivery vector based on the pHLIP peptide.

PNAs essentially comprise nucleobases joined by intramolecular amide bonds that form a backbone imparting stability, nuclease resistance, and increased binding affinity for complementary nucleic acids, according to the Nature report.

"We hypothesized that pHLIP would facilitate the intracellular delivery of charge-neutral PNA [miRNA inhibitors], which lack anionic phosphodiester groups, to cells within the tumor microenvironment," Slack and his colleagues wrote.

They focused their efforts on miR-155, a miRNA implicated in a variety of biological processes and whose overexpression has been linked to apoptotic resistance in cancers. After demonstrating that pHLIP-PNAs could be delivered to multiple cancer cell types in vitro, crossing plasma membranes under acidic conditions such as those found in solid tumors, the researchers explored their activity in vivo.

In a mouse model of lymphoma, treatment resulted in suppression of miR-155. In mice with implanted tumors overexpressing the miRNA, the drug slowed tumor growth and imparted a survival advantage without signs of toxicity or renal damage.

Although the pHLIP approach is limited to drug payloads with limited charges such as PNAs, it has wide applicability for targeting the tumor microenvironment and offers new opportunities for targeted miRNA silencing, the Yale investigators concluded.

The Scan

Positive Framing of Genetic Studies Can Spark Mistrust Among Underrepresented Groups

Researchers in Human Genetics and Genomics Advances report that how researchers describe genomic studies may alienate potential participants.

Small Study of Gene Editing to Treat Sickle Cell Disease

In a Novartis-sponsored study in the New England Journal of Medicine, researchers found that a CRISPR-Cas9-based treatment targeting promoters of genes encoding fetal hemoglobin could reduce disease symptoms.

Gut Microbiome Changes Appear in Infants Before They Develop Eczema, Study Finds

Researchers report in mSystems that infants experienced an enrichment in Clostridium sensu stricto 1 and Finegoldia and a depletion of Bacteroides before developing eczema.

Acute Myeloid Leukemia Treatment Specificity Enhanced With Stem Cell Editing

A study in Nature suggests epitope editing in donor stem cells prior to bone marrow transplants can stave off toxicity when targeting acute myeloid leukemia with immunotherapy.