According to Northwestern Medicine researchers, the brain is the main target of ALS (amyotrophic lateral sclerosis). This flips a long-standing belief that the disease begins in the spinal motor neurons and any treatment must target the spine as the key focus.
A new Northwestern study shows the degeneration of the brain motor neurons (the nerve cells of the brain that control the movement of the legs) is not just an outcome of degeneration of spinal motor neurons, as had been previously thought.
We have discovered that the brain degenerates very early in diseases like ALS and sends us warning signals and shows defects early in the disease. If we wish to develop long-term and efficient treatment strategies, we need to repair motor neurons in the brain. The brain is essential in ALS.
Hande Ozdinler, lead study author and associate professor of neurology, Northwestern University Feinberg School of Medicine
The paper will be published on Dec. 2 in Gene Therapy.
ALS is a fatally fast-growing neurodegenerative disease that can cause paralysis to its victims.
More than 250,000 people are affected by upper motor neuron diseases like ALS, hereditary paraplegia, and primary lateral degeneration each year in the United America alone. There is no cure or long-term treatment.
This is the first study that clearly shows motor neuron loss in the brain is not a result of spinal motor neuron diseases, but is a result of a different cause.
The study is also the first to show that the gene UCHL1 is crucial in maintaining the health of motor neurons that are diseased due to two independent underlying causes. One is the accumulation of poorly folded proteins, and the second is the accumulation of sticky protein clumps in the cells. These problems are found in more than 90% ALS cases as well as in other cases of upper motor neuron disease.
“Our findings not only give the evidence to target brain motor neuron health in ALS as a therapeutic intervention, it also uncovers the first target gene that could help these neurons be revitalized,” Ozdinler said.
“This has huge clinical implications,” Ozdinler said. “Being in a position to alter gene expression in diseased brain motor neurons in upper motor neuron disease patients is mind boggling. Because movement begins in the brain, we can keep brain motor neurons healthy and healthy by directing gene delivery. This will enable us to create personalized treatment options for patients suffering from upper motor nerve disease.
Northwestern University scientists have previously identified NU-9, the first substance that reverses the ongoing degeneration of upper motor neurons which are prone to disease and are a key contributor to ALS. The study now exposes the importance and importance of treating upper motor neurons in ALS and identifies the first genetic target.
The next step is to determine the most effective dose and the most appropriate location of injection with respect to improvement of movement and reduction of disease conditions in at least two different ALS disease models. Scientists will translate the findings of preclinical toxicology research into the clinical trial. This process is likely to take a long time.
Genc, B., and. (2021) Upper motor neurons are targets for gene therapy and UCHL1 is essential and sufficient to enhance the cellular health of damaged motor neurons of the upper region. Gene Therapy. doi.org/10.1038/s41434-021-00303-4.
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