by A team of neurobiologists led by Prof. Dr. Hilmar Bading at Heidelberg University has made a significant breakthrough in the study of amyotrophic lateral sclerosis (ALS), a degenerative disease that affects the nervous system. The team has examined a neuroprotective molecule from a novel drug class that has shown promising results in a mouse model of ALS and in brain organoids of ALS patients. The findings of their study have been published in the journal Cell Reports Medicine.
ALS is a debilitating disease that specifically targets motor neurons and leads to the progressive loss of muscle control. As the disease advances, the nerve cells responsible for voluntary muscle movement die, resulting in muscle wasting, difficulty in speaking and swallowing, and eventually respiratory failure. Unfortunately, there is currently no effective drug treatment for ALS, and most patients die within two to five years after diagnosis.
The molecule used in the study, FP802, belongs to a new class of drugs known as TwinF interface inhibitors. These inhibitors, discovered by Prof. Bading and his team at the Interdisciplinary Center for Neurosciences (IZN) of Heidelberg University, disrupt the physical interactions of two ion channel proteins – the NMDA receptor and TRPM4. These proteins form a protein-protein complex, and their interactions have been found to play a role in the progression of ALS.
NMDA receptors are found on the surface of nerve cells, both within and outside the synapses, which are the contact points between nerve cells. While the stimulation of synaptic NMDA receptors contributes to learning and memory processes and the protection of nerve cells, their activation outside the synapses leads to the death of nerve cells. The previous research conducted by Prof. Bading’s team revealed that the TRPM4 protein enhances the toxic properties of extrasynaptic NMDA receptors in the brain, forming a death complex that is linked to ALS.
The neuroprotective molecule FP802 targets the TwinF protein pocket of TRPM4, blocking the interaction between NMDA receptors and TRPM4 and disrupting the formation of the death complex. The researchers conducted studies using an ALS mouse model and brain organoids derived from ALS patients and found that the administration of FP802 prevented cell death and the loss of spinal motor neurons in mice. The treatment also improved motor abilities, slowed down disease progression, and significantly extended the lifespan of the animals.
Prof. Bading is hopeful about the therapeutic potential of this new drug principle in the fight against neurodegenerative diseases. He foresees the development of TwinF interface inhibitors for use in patients, and in collaboration with FundaMental Pharma, a biotech startup affiliated with the IZN Department of Neurobiology, the molecule FP802 will be optimized and tested in clinical trials in the coming years. Dr. Jing Yan, who played a role in the research, has recently joined FundaMental Pharma to spearhead the further development of FP802.
The discovery of a novel and effective treatment for ALS patients would be a major breakthrough. By inhibiting the interaction between NMDA receptors and TRPM4, the researchers have shown great promise in preventing the death of motor neurons and slowing down the progression of the disease. This research offers hope to ALS patients and their families, and further development of this drug principle could potentially lead to significant improvements in their quality of life.
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1. Source: Coherent Market Insights, Public sources, Desk research
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