New research from the MRC Laboratory of Medical Sciences (LMS) provides a powerful, scalable method for finding treatments for rare genetic diseases using tiny, transparent worms.
The study, led by Dr. André Brown and the Behavioral Phenomics group at the LMS, is published in BMC Biology. It represents a step toward solving a major challenge in medicine: how to develop treatments for the thousands of rare genetic diseases that currently have none. The work builds on a previous study published earlier this year in eLife, and together they mark a shift in how we can model these diseases and test potential treatments at scale.
The rare disease paradox
Rare diseases may be individually uncommon, but together they affect millions of people worldwide. With over 7,000 known rare genetic disorders, fewer than 10% have approved treatments. One of the main obstacles? Economics.
Developing a new drug from scratch typically takes 10 years and costs about $2.5 billion. For diseases that affect just a handful of patients, traditional pharmaceutical investment simply doesn’t add up. That’s left most rare disease families with little more than a diagnosis and no clear path forward.
A scalable alternative: Worm avatars
Enter Caenorhabditis elegans, a tiny nematode worm with surprising power. Using this microscopic organism, researchers can now rapidly create genetic “avatars” of rare diseases—worms engineered to carry the same genetic mutations as human patients.
Worm models of disease are not new, but what sets this latest work apart is the systematic, high-throughput approach the team has developed. By using advanced imaging and behavior-tracking tools, they can now quantify subtle movement differences in mutant worms—what they call “behavioral fingerprints”—and use those signatures to test the effect of hundreds of existing drugs.
This is particularly beneficial because many rare diseases affect the nervous system meaning there are often behavioral phenotypes, not just developmental phenotypes, which are harder to see by eye.
Why drug repurposing?
Instead of starting from scratch, the researchers are focused on repurposing existing drugs—ones already shown to be safe in humans. That dramatically speeds up the path to the clinic.
It’s not just theoretical. The drug Epalrestat made it from a worm model to a Phase III clinical trial in just five years, at a fraction of the typical cost—roughly $5 million. Another compound, Ravicti, followed a similar trajectory after being identified in an initial worm screen.
What’s new in the latest study?
While the first study, published in eLife in January, focused on gene knockouts—completely disabling certain genes—the latest paper takes things a step further. It introduces patient-specific mutations into the worms, mimicking the exact DNA changes found in individuals with ultra-rare conditions.
“These models are closer to what’s actually happening in patients,” explains André. “And we’ve shown that our behavioral phenotyping method works across a wide range of these models.”
The team’s goal now is to extend this approach to thousands of diseases.
The promise is enormous. The team believes that with sufficient investment, it would be possible to create worm avatars for every rare disease with a conserved gene and systematically screen existing drugs for therapeutic effects.
In the long term, that could mean faster, cheaper access to treatments for families who currently have no options.
“It’s a different approach to disease modeling—cheaper, faster, and more scalable. We still have a lot to learn, and not every model will lead to a treatment,” says André “But we now know it’s possible to do this systematically. That’s a new opportunity.”