AstraZeneca and Ionis target diabetes with antisense approach to regenerating pancreatic cells

by Arlene Weintraub | 

Oct 22, 2018 11:04am

Type 2 diabetes is caused by a progressive loss of insulin-producing beta cells in the pancreas, and current remedies can’t do much beyond just relieving symptoms. Now AstraZeneca and Ionis are working together to investigate a new way to target beta cells with antisense oligonucleotides (ASOs)—and they have early evidence the approach may help restore the functioning of those vital cells.

ASOs are synthetic polymers designed to target RNA and modify the production of disease-causing proteins. Historically scientists have struggled to deliver ASOs to cells beyond the liver, so the AZ-Ionis team had to come up with a way to get them into the pancreas.

To do that, they tagged the ASOs to a protein to glucagon-like peptide 1 receptor (GLP1R), which is expressed on pancreatic beta cells. This allowed them to deliver the ASOs directly to the cells, where they silenced genes that contribute to hampered insulin production, they reported in the journal Science Advances. The technique did not affect off-target cells in the pancreas or other organs.

The team went on to test the ASOs in mice, with doses given either intravenously or by injection. Both methods were equally effective at promoting uptake by beta cells. When they compared mice that received the ASOs weekly for six weeks to those that got saline injections, they found the treated mice had lower levels of a protein that contributes to compromised insulin production.

The research is part of a deal AstraZeneca formed with Ionis in 2015 to develop antisense therapies for metabolic, cardiovascular and renal diseases. In February of this year, AstraZeneca paid $30 million to license one drug candidate that emerged from that pact, IONIS-AZ5-2.5Rx, to treat a form of kidney disease. Then, in April, it handed over another $30 million to develop IONIS-AZ6-2.5-LRx in nonalcoholic steatohepatitis (NASH).

The two companies first teamed up in 2012 to investigate RNA therapies for cancer. The relationship has experienced some bumps, though, including a 2016 decision by AstraZeneca to ditch an Ionis drug it had been investigating in prostate cancer.

AstraZeneca is optimistic that ASOs will offer an entirely new approach to treating Type 2 diabetes, the company said in a statement. “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,” said Carina Ämmälä, the study’s leads author and a team leader in AstraZeneca’s IMED Biotech Unit.

https://www.fiercebiotech.com/research/astrazeneca-and-ionis-target-diabetes-antisense-approach-to-regenerating-pancreatic-cells?itx[idio]=8812325&ito=792&itq=1c636c52-6d49-49d8-aae1-5f9e8d651ea9