AstraZeneca shows potential of gene silencing in pancreatic cells

Research published in Science Advances shows first functional delivery of antisense oligonucleotides to pancreatic beta-cells in vivo

AstraZeneca today announced breakthrough research that enables genes to be ‘silenced’1 specifically in insulin-secreting pancreatic beta-cells using targeted delivery of antisense oligonucleotides (ASOs) in in vivo models. This represents the first example of targeted delivery of ASOs to a tissue other than the liver and opens the possibility of this drug modality to develop future treatments for a broader array of diseases. The pioneering approach was published in Science Advances.1

ASOs are a drug modality with disease-modifying therapeutic potential which has historically been limited by delivery challenges since they are too large to passively diffuse into cells and many cell types will not actively internalise them.2 This new research demonstrates how uptake of ASOs into pancreatic beta-cells can be enabled by tagging them to a protein (peptide conjugation) recognised and internalised by the glucagon-like peptide 1 receptor (GLP1R) which is highly expressed on pancreatic beta-cells.1

Researchers found in preclinical models the ASO target gene in the beta-cell could be silenced without affecting gene expression in other cells in the pancreas, liver or other tissues. This indicated that this technique is highly specific for cell types expressing GLP1R.

Carina Ämmälä, former Team Leader in Cardiovascular, Renal and Metabolism (CVRM) at AstraZeneca said: “This pre-clinical proof-of-concept study opens new possibilities for the use of ASOs to treat diseases affecting pancreatic beta-cells, such as type-2 diabetes. Current available treatments for diabetes can control the symptoms but do not modify the disease and most patients experience a progressive loss of functional beta-cells leading to reduced insulin secretion and worsening of the disease. Our goal is now to further explore the possibility of using targeted delivery ASOs to create a regenerative treatment that could restore beta-cell function.”

The study was conducted as part of AstraZeneca’s collaboration with Ionis Pharmaceuticals to discover and develop novel antisense therapies for cardiovascular, renal and metabolic diseases.

Brett Monia, Ph.D., chief operating officer at Ionis said: “This work highlights the potential of Ionis’ antisense technology and its ability to potentially deliver targeted antisense oligonucleotides to specific cell types throughout the body, cells that were previously considered unreachable.

Through our collaboration with AstraZeneca, we are making great progress towards discovering new ways of getting life-changing therapeutics to patients.”

About Antisense oligonucleotides (ASOs)

ASOs are a new class of therapeutic molecules. They are short, chemically modified, single-stranded nucleic acids that can target any gene product of interest.

ASOs offer new opportunities for therapeutic intervention because they act inside the cell to influence protein production. They do this by targeting ribonucleic acid (RNA) to either prevent the production of disease-causing proteins, increase the production of proteins deficient in disease, or target toxic RNAs that are unable to generate proteins. Antisense drugs are also able to target emerging biology mediated by microRNAs and long, non-coding RNAs. In recent years ASO-based treatments have been approved for spinal muscular atrophy and Duchenne muscular dystrophy.2


1 Ämmälä C, et al. (2018). Targeted delivery of antisense oligonucleotides to pancreatic beta-cells. Science Advances 4(10): eaat3386

2 Kaczmarek J, et al. (2017). Advances in the Delivery of RNA Therapeutics: From Concept to Clinical Reality. Genome Medicine. 9:60.