1 million Euro for research into Charcot-Marie-Tooth disease
Albena Jordanova receives Generet Prize for rare diseases
People living with Charcot-Marie-Tooth (CMT) disease may receive a diagnosis, but there is no treatment, and very often even the real cause remains unclear. Prof. Dr. Albena Jordanova (VIB-UAntwerp) has spent years working alongside affected families to find answers. She has now been awarded the Generet Prize for Rare Diseases, providing €1,000,000 in research funding to accelerate her team’s work on this rare inherited nerve disorder.
Charcot-Marie-Tooth disease or CMT affects the peripheral nerves, the long nerves that connect the spinal cord to muscles and sensory organs. As these nerves degenerate, patients experience progressive muscle weakness and wasting starting in the feet and hands, loss of sensation, pain, and gait problems. Walking long distances, climbing stairs, buttoning a shirt, or carrying groceries can all become increasingly difficult. Many patients need braces or mobility aids to move, and can eventually end up in a wheelchair. Fatigue and chronic discomfort are a daily reality.
“While the condition starts with small changes in balance and strength, it never stops progressing,” writes Carole Haislip, a 82-year old grandmother, whose 7 children and herself all have CMT.
The disease often runs in families, which can weigh heavily on decisions about work, independence, and family planning. Patients and relatives may share the same pressing questions: How fast will it progress? What can I still do? And will there ever be a treatment for CMT?
Three families across two continents
Albena Jordanova’s long-term commitment to this disease began almost two decades ago, shortly after she completed her PhD and set out to study inherited peripheral neuropathies. Working closely with the clinical teams of Prof. Tournev and Prof. Litvinenko at the Medical University-Sofia in Bulgaria, she came in contact with families whose disease remained unexplained.
“We realized there was a very large family with a peripheral neuropathy of unknown type,” she recalls. “For four years, we travelled the country with a clinical team, door to door, village to village, to sample this family.”
The work was painstaking and personal: mapping who was related to whom, reconstructing family histories across generations, and returning again and again to complete the picture. “Genetic research takes you places,” Jordanova says, describing weekends and summers spent collecting samples, sometimes in difficult conditions.
Over time, the team reconstructed a family tree spanning seven generations with more than 90 affected individuals. Many were impacted from childhood and became severely disabled in adulthood. When Jordanova relocated to Antwerp, she started studying a Belgian family with CMT, and continued her search for the genetic cause. In parallel, a large family with over 70 affected individuals across eight generations in the United States had been followed for decades by Prof. Florian Thomas and his team at the Hackensack Meridian School of Medicine.
Eventually, these efforts converged: families in all three countries turned out to have a mutation in the same underlying gene: YARS1.
Unravelling a disease mechanism
The YARS1 gene produces an essential protein that is needed in every cell of our body. Yet the disease mainly targets the peripheral nerves. That is what makes YARS1-linked CMT so scientifically intriguing.
Unlike many genetic diseases, YARS1 mutations do not simply switch off the protein’s normal function. Instead, evidence suggests they may introduce harmful “new” effects. What those effects are, and how they lead to progressive nerve degeneration, remains unclear.
Jordanova’s team believes that mutant YARS1 may be toxic in a location-specific way, particularly in the long nerve fibres that are under exceptional stress over a lifetime. By identifying the earliest molecular changes in affected nerves, the project aims to reveal which cellular pathways are disrupted and how exactly the degeneration begins.
Donated nerve tissue
Thanks to the generosity of families in Bulgaria and the United States, Jordanova’s team has access to an exceptional collection of peripheral nerves and other tissues, including material from affected individuals and from healthy controls.
“We have a unique starting point: the patients and their affected nerves,” Jordanova says. “Our ambitious project is only possible through the generous attitude of all these patients who donated material.”
The patient material includes samples from Carole Haislip’s family members. “Over the years, we have supported Professor Jordanova’s and Prof. Thomas’ work on our condition by making ourselves available for clinical evaluations, genetic testing, skin biopsies, etc.,” she says. “We understand that progress in this field depends on access to well-characterized patient samples, which is why both affected and unaffected adult members of our family are committed to supporting this research.”
Using advanced molecular profiling, the team will map which genes are active and which molecular signals are altered right at the sites where disease begins. Changes can be different in the most distant parts of long nerves compared to regions closer to the nerve cell body. Understanding those differences can offer crucial clues about why degeneration starts at the tips of the neurons and spreads towards the cell body.
The project will also use patient-derived neurons grown in the lab (reprogrammed from blood cells) to test whether discoveries from nerve tissue show up in a human cell system that can be studied repeatedly and in detail.
Fruit flies
Patient tissue can reveal what is wrong, but it is too scarce for large-scale testing. That is why Jordanova’s lab combines patient material with experimental models, especially fruit flies (Drosophila melanogaster), where the team pioneered the first CMT model.
“In flies carrying the mutant gene, we observe clear movement problems and nerve degeneration that mirror key aspects of the human condition,” explains Jordanova. The advantage of flies is speed and scale, she adds: “Experiments that might take years in other systems can be explored much faster. We can test hypotheses, and we can test drugs.”
Findings can then be cross-checked in patient-derived human nerve cells using a sophisticated bioinformatic analysis in collaboration with Dr. Csilla Varnai from the University of Birmingham, UK. Promising leads can eventually move further along the pipeline toward mammalian models and, ultimately, clinical translation.
Crucially, YARS1 is not the only CMT gene. It belongs to a group of genes called aminoacyl-tRNA synthetases, and several members of this group are already linked to CMT. That raises the possibility that solving the YARS1 puzzle will uncover mechanisms that apply across multiple rare neuropathies.
Carole Haislip: “The knowledge that our contributions might directly help to identify how molecular changes in the various types of CMT cause disease, and to test potential treatments, gives us hope, also for future generations of our and other families, who might otherwise face the same progressive and currently untreatable disease as we.”
In need of answers
For Albena Jordanova and her team, the funding provided by the Generet Prize means they can scale up the analyses of patient samples and disease models, generate richer datasets, and move faster from observation to testing.
Rare disease research can have an outsized impact. By zooming in on well-defined genetic cases, researchers can uncover mechanisms that may later inform research into other neurological disorders, including the more common acquired nerve damage seen in diabetes, chemotherapy, or alcohol-related neuropathies.
“This is the power of rare disorders,” Jordanova says. “The impact can be enormous.”
For Jordanova personally, it is also a milestone that strengthens her ability to pursue a long-term research vision built around close engagement with patient communities.
“The urgency of rare disease research is not theoretical,” she says. “Patients like Carole contact me directly and ask if there is any progress. With the Generet Prize, we can finally scale up the work and push the next steps faster.”
