A new pharmacological inhibitor can interfere with a central cell death mechanism responsible for motor neuron death and therefore critical for the progression of the motor neuron disease amyotrophic lateral sclerosis (ALS). A research team led by Professor Dr. Dr. Hilmar Bading, a neurobiologist at Heidelberg University, tested a neuroprotective molecule that belongs to a new drug class. It is able to inhibit specific protein interactions and has been successfully tested in a mouse model of ALS and in brain organoids of ALS patients. “On the long road to an effective treatment for ALS patients, these results from basic research may represent a significant step forward,” said Prof. padding.
ALS is a degenerative disease of the nervous system that specifically affects and damages motor neurons. As the disease progresses, the nerve cells that control voluntary muscle movement die. This leads to a progressive wasting of the muscles responsible for movement and speaking, but also for eating and breathing. To date, Professor Dr. Worse, there are no effective drug treatments for ALS patients, who mostly die within two to five years of diagnosis.
The FP802 molecule that the Heidelberg scientists used in the study belongs to a new pharmacological class of drugs. These are “TwinF Interface Inhibitors”, discovered by Prof. Dr. Bading and his team at the Interdisciplinary Center for Neurosciences (IZN) at Heidelberg University. These inhibitors disrupt the physical interaction of two ion channel proteins called NMDA receptors and TRPM4, which, due to a so-called protein pocket called “TwinF” by the Heidelberg scientists, form a protein-protein complex.
NMDA receptors are found on the cell surface of nerve cells and are present both at synapses, points of contact between nerve cells, and outside these points of contact. They are activated by a biochemical messenger substance, the neurotransmitter glutamate. Stimulation of synaptic NMDA receptors in the brain contributes to learning and memory processes as well as protecting nerve cells. But outside the synapse, activation of these receptors leads to nerve cell damage and death. The team around Hilmar padding has explored the reason for this in previous studies. They discovered that TRPM4 confers toxic properties on extra-synaptic NMDA receptors in the brain. Together, these two proteins form a “death complex,” which also plays a role in ALS.
The neuroprotective molecule FP802 binds to the TwinF protein pocket of TRPM4, blocking the contact sites of the interacting proteins and thus disrupting the lethal complex of the NMDA receptor and TRPM4. The Heidelberg scientists studied the principles of this new drug using an ALS mouse model as well as brain organoids from ALS patients. “We were able to achieve remarkable results with this completely new therapeutic concept in the fight against neurodegenerative diseases,” said the professor. padding. The scientist explained that it was possible to prevent cell death and therefore damage to the spinal motor neurons of mice by giving the neuroprotectant. This treatment improved their motor abilities, slowed disease progression and increased the animals’ lifespan.
The discovery of this new pharmacological class of drugs opens a promising avenue for combating ALS. A long-term goal is to develop TwinF interface inhibitors for use in patients.”
Hilmar Bading, Interdisciplinary Center for Neuroscience (IZN) at the University of Heidelberg
In close collaboration with the startup Fundamental Pharma, a biotech arm of the IZN Neurobiology division, the FP802 molecule will be optimized for human use in the coming years and tested for efficacy in clinical trials. Dr. Jing Yan, who was involved in the latest study, recently joined FundaMental Pharma to accelerate further development of FP802.
The research was funded by the German Research Foundation, the European Research Council and the Alexander von Humboldt Foundation. The results were published in the journal “Cell Reports Medicine”.
Yan, J., etc (2024). TwinF interface inhibitor FP802 halts motor neuron damage and slows disease progression in a mouse model of ALS. Cell Report Medicine. doi.org/10.1016/j.xcrm.2024.101413.