Gene discovery to improve drug safety

Researchers from Murdoch University have assisted in a groundbreaking discovery which could lead to the dramatic improvement of drug safety.

Drug hypersensitivity experts Professors Elizabeth Phillips and Simon Mallal from Murdoch’s Institute for Immunology and Infectious Diseases were among an international team whose findings show how some drugs cause allergies. The findings, which were published in the Proceedings of the National Academy of Science on 29 May, could lead to a new way of screening drugs for their potential to cause life-threatening reactions before their use in people.

The study, which was led by Dr Bjoern Peters from the La Jolla Institute for Allergy and Immunology in the United States, shows specifically how the HIV drug abacavir interacts with the human gene HLA-B*5701 and causes the immune system of patients carrying this gene to mount an attack on the patient’s body, much like what is seen in those rejecting a transplant organ.

HLA is a group of genes that have evolved to help our immune system to identify when our bodies are infected by foreign invaders such as viruses and bacteria. Individuals have different variations of HLA and many serious allergic reactions to drugs have been recently found to be linked to a specific HLA type. In the case of abacavir, the majority of people who carry the HLA-B*5701 variant will develop a potentially fatal drug allergy, a type of drug hypersensitivity.

“HLA-linked hypersensitivity is a really big problem that can produce symptoms ranging from mild rashes with flu-like symptoms to life-threatening rashes of the magnitude of a severe burn, organ failure and even death,” explained Professor Phillips.

“We are hopeful that our enhanced understanding of HLA-linked hypersensitivities will contribute to the identification of drugs likely to cause these reactions in the early stages of development and before their use in man.

“Our findings will also allow new drugs to be designed so that the most dangerous forms of drug allergy can be avoided.

“Drugs may either not make it to market or may be later withdrawn because of the occurrence of serious drug hypersensitivity in humans. Prescreening of drugs before use in man would allow drug makers to circumvent this risk and would enormously improve the safety and efficiency of drug development.”

Dr Peters and his team have developed tests that can be done on human blood samples to determine if a specific HLA variant is to blame for hypersensitive reactions to certain drugs.

“This type of testing could be done before human subjects are exposed to the drug and could lead to the design of drug variants that do not have this effect; or, if this is not possible - to ensure that only individuals who do not have this HLA variant are given the drug, as is now done for abacavir,” he said.

Abacavir was used in the study because it had previously been shown to cause a severe hypersensitivity reaction exclusively in patients with the HLA-B*5701 variant.

Professors Mallal and Phillips discovered and have been championing the use of HLA-B*5701 testing to prevent abacavir hypersensitivity since 2002.

“We are thrilled to see that the connection between HLA-B*5701 and abacavir hypersensitivity has provided us a roadmap for the use of personalised genetic medicine to improve drug safety in everyday clinical practice around the world and is now also providing us a roadmap for safer drug design and development,” added Professor Phillips.