Gene therapy saves nerves
Long processes of nerve cells – axons – form a kind of "wiring" of the nervous system, which transmits electrical signals that connect the brain with all parts of the body. When axons are damaged as a result of trauma, various pathological processes, under the influence of antitumor chemotherapy and other factors, a program is launched leading to their self-destruction. Apparently, it is this destructive effect that plays an important role in the development of many neurodegenerative conditions, including peripheral neuropathy, Parkinson's disease and amyotrophic lateral sclerosis (Charcot's disease).
Researchers at the University of Washington Medical School, working under the guidance of Professor Jeffrey D. Milbrandt, have developed a method of gene therapy that blocks this process. In experiments on mice, its use prevented the destruction of axons, which indicates the possibility of using this therapeutic strategy to prevent the death of neurons in many conditions, including peripheral neuropathy.
Peripheral neuropathies are the most common type of neurodegenerative diseases in the world. They can cause chronic pain, numbness, burning, itching and muscle weakness. Many neuropathies lead to the destruction of nerve fibers and to date there are no approaches that directly block this process. In many cases, it is not possible to slow down the progress of the disease and the possibilities of doctors are limited by attempts to alleviate the symptoms. To date, some progress has been made in suppressing neuropathic pain, but it is extremely difficult to weaken the feeling of numbness of the extremities.
Both physical and chemical damage to axons leads to activation of the SARM1 protein, which is inactive in healthy nerve fibers. In earlier studies, researchers have shown that the activation of SARM1 triggers the process of axon self-destruction, which is the end result of a chain of events that quickly consume all the energy reserves of the nerve cell. The axons of such cells literally disintegrate into fragments.
As part of their latest study, the authors used a virus harmless to the body to deliver a mutant version of the gene encoding the SARM1 protein into cells. The protein product of this gene blocks the rapid depletion of energy reserves characteristic of the disease and the subsequent destruction of axons even in the most severe forms of damage – complete nerve cutting.
Fig. 1 Cross-section of the sciatic nerve of an untreated mouse five days after the nerve was cut.
Fig. 2. A section of the sciatic nerve of a mouse that received gene therapy that blocks axon destruction. A micrograph taken five days after the injury shows many preserved axons (red).
Professor Milbrandt emphasizes that the mutant version of the protein used not only does not have a detrimental effect, but also suppresses the activity of the normal form of the protein that has already been activated in response to damage. He also notes that for a long time gene therapy has remained a pipe dream, but today a number of gene therapy methods are already undergoing clinical trials for the treatment of various diseases.
For example, a similar approach using a viral carrier is undergoing clinical trials as a method of treating Duchenne muscular dystrophy. In this disease, a different protein, but the same viral vector, is used to prevent muscle tissue atrophy.
Theoretically, it is possible to find a way to change the contents of carrier viruses so that they selectively deliver their genetic cargo to various types of cells, for example, to sensitive neurons in peripheral neuropathy and motor neurons in amyotrophic lateral sclerosis.
In addition to exploring the possibilities of experimental gene therapy, the authors are searching for other methods of blocking the activity of the SARM1 protein, including the search for small molecules for subsequent drug development.
Article by Geisler S et al. Gene therapy targeting SARM1 blocks pathological axon degeneration in mice is published in the Journal of Experimental Medicine.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Washington University School of Medicine in St. Louis: Gene therapy targeting SARM1 blocks pathological axon degeneration in mice.