“We analyzed the genomic profile of more than one million cells from 1,000 people to identify a fingerprint linking genetic markers to diseases such as multiple sclerosis, rheumatoid arthritis, lupus, diabetes type 1, spondyloarthritis, inflammatory bowel disease and Crohn’s disease,” says Professor Joseph Powell, co-lead author at the Garvan Institute of Medical Research. “We were able to do this using single-cell sequencing, a new technology that allows us to detect subtle changes in individual cells,” he says.
This discovery could help individuals find tailored treatments that work for them and guide the development of new drugs.
The study by researchers in Sydney, Hobart, Melbourne, Brisbane and San Francisco helps us understand why certain treatments work well in some patients, but not in others. This is the largest study to date to link disease-causing genes to specific types of immune cells.
A trial is currently underway in Sydney with Crohn’s disease patients to predict which treatments will work for specific patients.
“Some autoimmune diseases can be notoriously difficult to treat,” says Professor Powell.
“Due to the complexity of our immune system and its considerable variation from individual to individual, we do not currently understand why a treatment works well in some people but not in others,” he says. .
The study links specific genes and types of immune cells to an individual’s disease, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes and Crohn’s disease.
This means that an individual’s unique genetic profile could be used to deliver tailored treatments to precisely tame their immune system.
“Our data also provide a new avenue for narrowing down potential drug targets. The potential health and economic impacts of this research are enormous,” says Professor Alex Hewitt, co-lead author and clinician scientist at the Menzies Institute for Medical Research at the University of Tasmania.
“Most rare genetic diseases are like a major car accident in the body – they are usually easy to identify and locate where they occur in the genome. But immune diseases are often more like traffic jams, where genetic changes that impede traffic are harder to identify specifically. This study helped us identify hotspots,’ says Professor Hewitt.
“The biggest insight from this work will be the identification of therapeutic targets and the definition of immune disease subpopulations, which can then refine clinical trials to assess drug efficacy,” he says.
Our body’s immune system is designed to fight off outside threats, but autoimmune diseases occur when our immune system targets our own healthy cells. They affect around one in 12 Australians, are incurable and require lifelong treatment to minimize damage.
Often patients will try many different treatments before finding the one that works for them.
“Some drugs may be very effective in only 15% of patients and are therefore not recommended as first-line treatment,” says Dr. Seyhan Yazar, co-first author of the study.
“We now have a way to link treatment response to an individual’s immune genetics – and potentially screen those 15% of patients even before a clinician administers treatment.”
The researchers say their data could reduce the risks associated with developing new treatments.
“Pharmaceutical companies may have hundreds of targets and need to make decisions about which ones to advance to Phase I clinical trials, knowing that 90% of potential drug candidates fail during clinical development,” says Dr José Alquicira-Hernández, co-first author. and researcher at the Garvan Institute.
“Understanding which cell types are relevant for a particular disease is essential for developing new drugs.”
A million cells reveal complexity and bring certainty
The study provides unique insights by examining the genes of individual immune cells on an unprecedented scale. He analyzed the genomics of more than one million individual immune cells from around 1,000 healthy individuals, exploring 14 different types of immune cells in total.
This individual approach paints a much clearer picture than previous studies that analyzed cells combined in a blood sample.
“The problem with bulk RNA analysis is that we only observe an average signal. But there is great variation in cell functions and the types of cells that allow the body to defend itself against attack,” says Dr. Yazar.
“The average analysis does not reflect what is happening in the full variety of immune cells.”
Integration into clinical trials
The results led to clinical trials.
“We are working on a Crohn’s disease study in collaboration with St George’s Hospital which will determine how a patient’s immune genotype affects their response to different treatments and are looking to establish new trials in a range of autoimmune diseases. says Professor Powell.
“This is an important step in Garvan’s pioneering OneK1K study to show how genetics contribute to immune disease risk at the cellular level.”