Frontotemporal dementia (FTD) is a devastating early-onset neurodegenerative disorder, after Alzheimer’s disease. Among its victims is a celebrity like Bruce Willis (in the image with his wife Emma), diagnosed in 2023. But there are also unknown patients under 45 years of age. The symptoms are often subtle and unpredictable, with behavioral changes, speech and communication problems (aphasia). Unfortunately, these worsen over time. Patients completely lose their identities, becoming like children, unable to formulate and pronounce words. Sometimes, they can suffer a final stage of parkinsonism and movement disorders. The main cause of FTD is genetic and it is for this reason that clinical trials focus on gene therapies that halt the disease progression. But, sometimes, gene therapies may be toxic. Today, after studies in animals and in vitro, European researchers finally tested a simple pill you can take by mouth in the first human phase 1 clinical trial to treat frontotemporal dementia.
The Core of The Study
Published in Nature on September 16, 2026, the study consisted of two parts: a preclinical investigation in mice and in vitro and a clinical study in humans. The preclinical studies were conducted in several laboratories in Denmark, the United Kingdom and the Netherlands.
In the human study, conducted at the Centre for Human Drug Research (CHDR) in Leiden, in collaboration with Leiden University Medical Center (LUMC) of Netherland, researchers administered an oral molecule called VES001 to 79 healthy patients for 7 days, with the goal of increasing progranulin (PGRN), a protein that diminishes in frontotemporal dementia and whose deficiency is involved in neuroinflammation and neurodegeneration. The human trial also served to test safety and tolerability of the pill.
Results
As regards security and tolerability of the new drug, results were fairly encouraging. No adverse effects were reported during the treatment, and mild side effects like headache and fatigue were not linked to the medication. Even more encouraging were the results on pharmacodynamic effects. The administration of VES001 two times per day, for seven days, increased progranulin levels of 49% in the blood and of 18% in the spinal fluid in humans.
The administration in mice raised progranulin levels both in blood and cerebrospinal fluid (CSF).
Moreover, the molecule was shown to easily cross the blood-brain barrier (BBB) in humans and mice, reaching the central nervous system without difficulty.
Positive effects were also highlighted in the preclinical in vitro study, where animal and human cells mixed with enzymes were shown to increase progranulin without destroying or reducing sortilin, the receptor that binds and destroys progranulin in the lysosomes (special organelles inside cells that have the task of cleaning and recycling cellular waste).
The Mechanism
Progranulin and sortilin, namely the protein and its receptor, have a close metabolic interaction. Sortilin captures progranulin to eliminate it. Is this process that in those who have genetic frontotemporal dementia leads to neural loss and neurodegeneration in particular cerebral areas which are responsible for language and communication (left lobe). FTD, in fact, in 30 – 50% of cases, has genetic roots, especially with GRN gene mutations that encode progranulin and cause a massive reduction of this protein, leading to the onset of the disease.
Relevance of the Study
The study is particularly relevant because, unlike monoclonal antibody treatment, the oral molecule does not suppress sortilin or its cellular receptors. Researchers verified this through a comparison between VES001 and the monoclonal antibody latozinemab. which, instead, downregulates both surface receptors and total quantity of sortilin, with the risk to alter cell homeostasis. This downregulation and alteration don’t occur with the new molecule, which turns off the interaction between progranulin and sortilin, but does not destroy the latter, and this way, it allows homeostasis, a condition that protects the stability of cells.
“This first-in-human study demonstrates that VES001, a novel and selective small molecule competitive inhibitor of sortilin, is safe and well-tolerated in healthy adults and produces dose-dependent increases in progranulin levels. These effects are consistent with preclinical findings showing potent, specific binding of VES001 to human sortilin and inhibition of the progranulin-sortilin interaction… VES001 is a promising first-in-class therapeutic candidate for genetic frontotemporal dementia. Its favorable safety profile, BBB penetration, and ability to elevate progranulin in humans, together with the mechanistic concordance between in vitro, in vivo, and clinical data, provide a strong rationale for advancing to studies in genetically defined patient populations. Future trials will determine whether sustained progranulin (PGRN) normalization translates into disease-modifying therapy,” the researchers stated in their paper.
Conclusion
This study is a real milestone because, for the first time, it has proved that an oral pill may be safe and well tolerated, able to penetrate the brain and raise progranulin levels in humans. The concrete hope this early finding brings with it is dedicated to FTD patients and their caregivers. As said, frontotemporal dementia went into the spotlight for the tragic diagnosis that involved actor Bruce Willis. In a recent interview, his wife, Emma Heming Willis, affirmed: “Sometimes, he seems like a child staring at an object with curiosity, simply observing it… It is not just a matter of dealing with an illness; it is about living with the gradual loss of aspects of a loved one, while that same person is still present. “It’s natural: we all want the people we love to be healthy, full of life, and to remain the same people they have always been,” Emma explained. “But frontotemporal dementia is a devastating disease that takes things away from you very slowly.”
Photocredit: The Telegraph
