Breakthrough offers hope for treatment of Lou Gehrig’s disease

A breakthrough that offers hope for the treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) has been made by researchers who identified a previously unknown mechanism involved in the development of the debilitating, fatal neurological disorder.The Tel Aviv University researchers found that the motor neurons of ALS patients are destroyed by muscular toxins. They have also found an innovative approach that is the basis for a possible future drug – a specific microRNA molecule silences the genes that cause toxin secretion.The research focuses for the first time on a specific microRNA, whose levels were found to decrease as a result of ALS-causing muscular mutations.ALS is a neurodegenerative disease that destroys nerve cells and causes permanent disability and death.The study was led by Dr. Eran Perlson of the physiology and pharmacology department at TAU’s Sackler Faculty of Medicine and conducted by TAU doctoral students Roy Maimon and Ariel Ionescu, in collaboration with Dr. Oded Behar of the Hebrew University’s department of developmental biology and cancer research. A paper on the breakthrough was recently published in the prestigious Journal of Neuroscience of the Washington, DC-based Society for Neuroscience.“While we are not claiming we have found the cure for ALS, we have certainly moved the field forward,” Perlson said.Asked to comment, Avichai Kremer, the founder and chairman of IsrA.L.S.-Prize for Life, which raises funds for ALS research, who has suffered from the disease for 14 years, told The Jerusalem Post: “The cause of ALS has been unknown, and this is the biggest impediment to developing treatments for the disease. If this is indeed the cause, then the researchers have accomplished something stupendous. I had always hoped an ALS research breakthrough will come out of Israel, and I hope some company will try to commercialize this approach soon. In the meantime, I would like to see the research team test its findings on more animal models of the disease.”Researchers have had much difficulty understanding the specific underlying mechanisms of ALS.Some have focused their efforts on the metabolism of microRNAs (miRs) – small molecules that regulate the translation of proteins and play an important role in many other cellular processes.Recent work has demonstrated that the alteration of miRs is involved in many neurodegenerative diseases, including ALS. The TAU study identifies a new mechanism related to ALS pathology in which the muscle secretes toxic molecules that kill axons and neuromuscular junctions and thus leads to muscle atrophy. It also found reduced levels of one specific miR – miR-126-5p – in ALS models, which cause a rise in the toxic molecules such as the axon-destabilizing type-3 semaphorins and their co-receptor neuropilins. Perlson and his team suggested that this new miR could one day be harnessed to treat ALS patients.“We demonstrated in lab work and on mouse models that we can successfully ameliorate ALS symptoms using this miR as a potential drug,” Perlson said. “We further demonstrated that muscle tissues – not only motor neurons – are undoubtedly involved in the progression of ALS. This point is particularly important, as it contradicts other theories in the field.”The TAU-led team worked on primary motor neuron and muscle tissue samples grown in silicon microchips to model the human motor unit. It discovered that genetic manipulation of the novel miRNA significantly slowed the neuron degeneration process. It then used transgenic ALS-model mice, injecting these with a virus carrying the novel miR126-5p, and found that the mice had recovered significantly.Muscle atrophy, neuromuscular function and ability to walk showed significant improvement, Perlson said.“We found that the specific overexpression of miR126-5p was beneficial for axon degeneration and NMJ disruption both in vivo in ALS mice models,” Perlson said. “We were able to pinpoint the fact that alterations in miR126-5p facilitate motor neuron degeneration.”The team next plans to conduct a comprehensive study involving other, nonmuscular tissues that are damaged by ALS. “Not only is the specific miR important here; the approach is also extremely important. Sometimes a nonconventional treatment is the right course of treatment.”