Imagine being told that your child has a rare brain disorder that doctors only began to understand a little over a decade ago. The condition slowly takes away abilities most of us take for granted, like walking, speaking, even eating, while no cure exists. For families living with POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), this is reality. But new research in RNA therapies is beginning to open doors where none existed before.
What is POLR3-related Hypomyelinating Leukodystrophy?
Dr. Geneviève Bernard is a clinician and researcher dedicated to advancing treatments and research for POLR3-HLD. She has been funded by D2R under the Translational Impact Research funding program for 3 million dollars for her project titled Innovative RNA therapies offer new hope for patients affected by POLR3-related leukodystrophy. Leukodystrophies are a group of rare, genetically inherited brain disorders that affect white matter, largely composed of myelin. Myelin insulates brain cells (neurons), ensuring they are protected and rapidly transmit signals. Neurons are like electrical wires in our body. The myelin acts as the protective coating around them, helping signals travel quickly and efficiently so the brain and body can communicate properly. In leukodystrophies, the myelin either doesn’t form properly during brain development or forms normally but later becomes damaged or sick. Leukodystrophies typically present in childhood, and over time lead to worsening disabilities. Sadly, many children with leukodystrophies do not survive the disease.
POLR3-HLD is a rare inherited leukodystrophy caused by changes in genes that build an important enzyme called RNA polymerase III, which helps produce small RNAs important for the health of our cells. Every cell in our body runs on instructions, like using a recipe book when cooking. For a given gene, the DNA (the gene) produces the RNA by a process called transcription. In children with POLR3-HLD, changes (damaged instructions) in the genes that make up part of RNA polymerase III prevent it from producing certain small RNAs that are essential for healthy cell function. As a result, in the developing brain, the myelin-producing cells are unable to form the essential myelin sheath. Until recently there was little hope of correcting the effects of these damaged instructions, but thanks to advances in RNA therapies researchers are finding new ways to fix the deleterious effect of those instructions, offering hope for families who have been waiting for answers.
Trying Different Therapeutic Approaches
Dr. Bernard’s research team is investigating three approaches to develop RNA-based treatments for POLR3-HLD. First, they are using antisense oligonucleotides, short strands of genetic material that attach to the cell’s RNA instructions like a guide, to reduce the number of harmful instructions in a patient’s cells. By latching on, they can redirect how the message is read, either by silencing harmful instructions or by helping the cell process the message in the correct way. Second, they aim to restore the function of a commonly mutated gene, POLR3A, which is an essential component of the cell’s RNA polymerase III machinery. They aim to do this by replacing the faulty RNA instructions with a healthy copy of the gene’s RNA. These healthy copies will be delivered using tiny fat-based carriers called lipid nanoparticles. Finally, they are exploring ways to boost the activity of RNA polymerase III, the enzyme disrupted in this disorder. They aim to do this by reducing a natural inhibitor of the enzyme, like taking the foot off a brake that normally slows it down.
For Dr. Bernard and her team, looking at three approaches not only provides a safety net if one approach fails, but also paves the way for a breadth of discoveries. With support from patients, advocacy organizations, and industry partners, the team hopes to move promising treatments quickly toward clinical trials. This project, however, much like any research, doesn't come without challenges. Knowledge surrounding POLR3- HLD is still growing, as the first mutations responsible for this disease were only discovered in 2011. Furthermore, clinical trials for rare diseases present difficulties with cost, recruitment, and patient selection. Dr. Bernard explains the D2R grant she’s received has alleviated some of those difficulties “This grant gives us the resources to accomplish a lot in a short period of time. For researchers working on rare disease, that is like a dream come true.”
Families at the Heart of POLR3-HLD Research
Dr. Bernard describes her path to studying leukodystrophies as a “happy accident.” She fell in love with these complex puzzles genetic disorders present, and the distinctive signatures they create in magnetic resonance imaging (MRI) scans. She describes their distinctness similar to looking out at an unmistakable horizon. “You look at an MRI and for many leukodystrophies, you know what the diagnosis is, like if you were to look at the Paris skyline in the dark, you see the lights on the Eiffel Tower, you think ‘it can only be Paris.’” Following her newfound passion, in her genetics rotations she explains that she felt deep compassion for the families navigating such difficult challenges and was determined to provide the best possible care. “Following families through this very difficult disease course is a privilege. To hear their stories and work together to try to make sure their children are as happy as possible for as long as possible, I feel useful when I do that.”
Dr. Bernard is doing the work for what matters most– the families that are affected at the heart of her work. She actively engages with patient and advocacy organizations to ensure that research priorities align with the needs of those living with these disorders. She explains that “Interacting with patients and their families is key for developing therapies that are relevant for them.
What we scientists think is significant may not be significant to them.” By listening closely to patients and caregivers, her team can shape research questions and therapeutic approaches that truly matter to the communities they serve.
Balancing rigorous science with the privilege of supporting families, Dr. Bernard finds meaning in both discovery and direct patient impact. “Of course we want to make progress as fast as possible,” she says. “Research is always slower than we want it to be, because in an ideal world we would have the therapy ready tomorrow.” Yet she sees her work as part of a larger shift toward personalized medicine: “Everything we’re doing now is leading to real, individualized treatments. It’s already happening, and soon we hope more families will benefit.”
