Antisense oligonucleotides (ASOs) hold incredible potential to be used as effective therapies for a wide range of diseases. One challenge in moving them from bench to bedside has been their limited ability to be taken up by target cells. A collaboration by AstraZeneca and Ionis Pharmaceuticals has made a huge advance in this area by exploiting a receptor and providing a new approach to delivering ASOs into pancreatic β-cells—cells that are notoriously recalcitrant to ASO uptake. The work is published in Science Advances in a paper titled, “Targeted delivery of antisense oligonucleotides to pancreatic β-cells.”
ASOs are short (14–20 nucleotides), synthetic, single-stranded oligodeoxynucleotides that can alter RNA and modify protein expression. Recent advances have been made to improve their potency, efficacy, stability, and pharmacokinetic properties. In this study, researchers have exploited a receptor to design a new approach to deliver ASOs to pancreatic β-cells. They combined ribonuclease H1- dependent ASOs with an engineered glucagon-like peptide-1 receptor (eGLP1R)—a receptor known for its internalization—to productively deliver ASO cargo to pancreatic β-cells both in vitro and in vivo.
The team used quantitative real-time polymerase chain reaction that targeted metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a noncoding RNA transcript expressed in many tissues, to determine that eGLP1-MALAT1-ASO conjugation enhanced the uptake of ASOs in vitro in human islets compared to MALAT1-ASO.
The ability of eGLP1-conjugated ASOs to target insulin-secreting β-cells within the pancreas was investigated in mice treated twice a week with skin injections of saline, MALAT1-ASO, or eGLP1-MALAT1-ASO and intravenous injections of MALAT1-ASO or eGLP1-MALAT1-ASO. Mice treated with eGLP1-MALAT1-ASO experienced ASO uptake and reduced MALAT1 gene expression in the pancreatic islets. The researchers also targeted the forkhead box protein O1 (FOXO1) transcript and found that eGLP1-FOXO1-ASO increased productive uptake in isolated mouse islets. Additionally, the doses used did not affect target gene expression in liver or other tissues, indicating enhanced tissue and cell type specificity.
First discovered over two decades ago, ASOs have developed as extremely promising therapies. ASOs are particularly exciting because of their ability to target genes coding for proteins linked to human diseases that are considered undruggable by more traditional methods such as small molecules. Indeed, two ASO-mediated therapies have received approval from the FDA for the treatment of two diseases that had extremely limited options in their therapeutic arsenal; Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). The researchers who developed the SMA therapy were announced as recipients of the 2019 Breakthrough Prize in Life Sciences earlier this week.
The authors write that “the findings presented in this paper have the potential to broaden the use of ASO technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of ASOs to additional cell types.” With the rapid development of improved delivery methods of ASOs, this technology may have a dramatic effect on the treatment of many conditions in the near future.