Lupus

Towards a pathway based diagnosis in lupus


Thanks to the availability and affordability of human genome sequencing we are tantalisingly close to being able to stratify lupus patients and target treatment, the conference has heard.

Keynote speaker Dr Carola Vinuesa a scientist at the Curtin School of Medical Research in Canberra says that if we can understand the precise molecular defects in each lupus patient we will be able to develop targeted therapies.

Until now lupus patients have been lumped together but we now know the disease is extremely heterogeneous, she explains.

For instance the fact that for a diagnosis a lupus patient needs to  meet four out of 11 diagnostic criteria suggests there are different pathways causing disease.

But until now it’s been difficult to work out what these pathways were because research focused on trying to identify pathways that were relevant in mice and then see if they were important in humans.

In the end researchers faced a “block in translation”, illustrated by the fact that over the last 50 years there has only been one new treatment approved for lupus.

So Vinuesa and her team took a personalised approach by utilizing human genome sequencing to look at every single mutation carried by individuals with lupus.

Using bioinformatics they were able to filter through thousands of variants to end up with a handful that could cause disease.

Through DNA editing technology they then introduced precise mutations found in the human genome either in a cell line or a mouse zygote.

“Within a few weeks instead of years we can generate a mouse that carries exactly the same mutations as the human…now we can have certainty about whether those mutations are really disregulating the immune system,” she explains.

Vinuesa says she thinks medicine is progressing to a new era of personalised medicine where each patient has their own syndrome, or may still share pathways.

“In the end we may be able to stratify patients into different sub-groups according to pathways,” she says.

Towards targeted treatment

The problem at the moment is that when a patient is diagnosed with lupus they go through a hierarchy of treatments with no particular stratification.

There’s also very little idea of which treatment will be effective in which patient, she says.

But if we identify biomarkers that can point to the affected molecular pathway and subgroup patients according to those biomarkers then we may be able to start patients on the right treatment for their particular type of lupus.

The beauty is those biomarkers will help stratify clinical trials as well, says Vinuesa.

“At the moment most clinical trials are failing because in order to demonstrate efficacy of the drug across the entire cohort,” she says.

“Suddenly we’ll start seeing many drugs for lupus already licensed for use,” she adds.

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