Combating gene targeting challenges

Problems and potential solutions have been identified with new gene targeting medicines that could change the way these are made to help patients.

Gene targeting medicines—nucleic acid therapeutics—are an emerging category of medicine with huge potential to improve the lives of patients. Based on synthetic nucleic acids (DNA and RNA), nucleic acid therapeutics target diseases at the genetic level, by preventing the expression of disease-causing proteins. This new category of medicines could benefit patients by replacing daily medication with injections administered only several times a year.

What are nucleic acids?

DNA and RNA are a category of molecules known as nucleic acids, which contain and access the genetic information controlling which cells do what in our bodies. Nucleic acids are present in every life form, including bacteria and viruses, and are essential for our immune system to detect infections.

Dr Michael Gantier, Nucleic Acids and Innate Immunity Research Group, Hudson Institute
Dr Michael Gantier

A study published in Nucleic Acids Research has established that common modifications used to stabilise these nucleic acid treatments are immunosuppressive, meaning that these treatments could selectively block some key sensors of our immune system which normally alert us to infections.

Led by Dr Michael Gantier and including PhD student Arwaf Alharbi and Masters student Aurelie Garcin, the study investigated how synthetic nucleic acid molecules interact with the body’s immune system.

“The immune-stimulatory effect of some nucleic acid therapeutics has been known for more than 15 years. However, how these molecules can block the immune response has been understudied,” said Dr Gantier.

“We discovered that one class of nucleic acids-based therapeutics was prone to unintended immune suppression, specifically, inhibiting a sensor called Toll like receptor 7 (TLR7),” Dr Gantier said.

How are these medicines being used?

Several nucleic acid medicines have recently been approved for use in humans, for instance treating some cases of muscular dystrophies. Others are in clinical trials targeting a range of conditions including neurological diseases, cancer, and hypercholesterolemia – which affects about one in 200 people. The therapeutics are also being used to develop anti-viral drugs.

“While these molecules are used to target a specific disease, they can also shut down some of the key sensors in the body’s immune response. This could cause strong side effects in patients infected by pathogens after injection with these molecules.”

“If a patient gets the flu or a bacterial infection a few days after getting an injection with nucleic acid therapeutics, this may put them at increased risk of infection. It will only be a problem when a patient gets an infection, so this is a new issue that has not been on researchers’ radar. However, as these technologies become more broadly used, there is an increased potential for patient complications,” Dr Gantier said.

Solutions identified

In addition to identifying the problem, the study has also found molecular designs that could be used to avoid these immunosuppressive effects, keeping the immune response in check to defend against infection.

“While we discovered a frequent problem with these molecules we have also provided molecular designs to solve it. This could change the way this new class of therapeutics is made, and help many patients.”

“Many new drugs currently in development based on nucleic acids could be affected,” he said.

Collaborators
Mark Behlke (IDT), Kim Lennox (IDT)

Funders
NHMRC, ARC, Fielding Foundation Fellowship and Innovation Awards.

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Research Group leading this work