Scientists develop new gene therapy that prevents axon destruction in mice

Nervous axons serve as wiring of the nervous system, sending electrical signals that control the movement and sense of touch. When axons are damaged, whether through injury or as a side effect of certain medications, a program is triggered that causes the axons to self-destruct. This destruction probably plays an important role in several neurodegenerative states, including peripheral neuropathy, Parkinson's disease and amyotrophic lateral sclerosis (ALS).

Scientists have developed gene therapy that blocks this process, preventing the destruction of axons in mice and suggesting a therapeutic strategy that can help prevent the loss of peripheral nerves under multiple conditions.

The study, from the Washington University School of Medicine in St. Louis, is published in the Journal of Experimental Medicine.

The strategy could help prevent peripheral neuropathy, a disease that currently affects about 20 million people in the United States. Peripheral neuropathy can result from chemotherapy for the treatment of cancer or poorly controlled diabetes. It causes persistent pain, numbness, burning, itching and muscle weakness.

"Peripheral neuropathies are the most common neurodegenerative diseases in the world," said lead author Stefanie Geisler, MD, badistant professor of neurology. "Many peripheral neuropathies are caused by the breakdown of nerve fibers, but we currently have no treatment that can directly block this process.For many neuropathies, we can not stop the progression of the disease and we just try We have managed to reduce the neuropathic pain, but it is very difficult to relieve the numbness.

"I see many patients with chemotherapy-induced neuropathy, and this can have a big impact on their quality of life," she said. "To benefit patients, we will need to test this treatment in clinical trials in humans, but our current results are significant because we have shown for the first time that we can effectively block the breakdown of nerve fibers." in mice with standard gene therapy. "

When an axon is injured, cut or crushed by injury or damaged by medication, a protein called SARM1 becomes active. In healthy nerves, this protein is turned off. Previous studies conducted by this research team have shown that activated SARM1 triggers the self-destruction of axons, triggering a chain of events that quickly consumes all the energy delivered to the nerve cell. The axons of such cells break into pieces.

In this study, scientists used a virus – a virus that can not cause disease – to transmit to cells a mutated version of the SARM1 protein that blocks the destruction of axons.

This mutated MRSA1 prevents the characteristic rapid loss of energy and the subsequent destruction of axons, even in the most extreme form of injury – a complete rupture of the axon.

"With our viral gene therapy, we have provided a mutated form of MRSA1 that is not only inactive but also blocks activated normal MRSA1 proteins in mice with nerve damage," said lead author Jeffrey D. Milbrandt, MD, Ph.D. James S. McDonnell Professor and Head of the Department of Genetics. "For a long time, viral gene therapy was a chimera, but many ongoing clinical trials in other diseases suggest that we are on a promising path."

For example, a similar viral gene therapy is currently undergoing clinical trials for a genetic disorder called Duchenne muscular dystrophy. In this case, a different protein is administered to treat muscle loss, but the virus is the same.

In theory, it might be possible to modify viral packaging for viruses to transmit their gene payload to different cell types – sensory neurons for peripheral neuropathy or motor neurons for ALS, for example.

"It could be transformative because it helps fight so many diseases," said co-author Aaron DiAntonio, MD, PhD, chair of the Alan A. and Edith L. Wolff Chair in Developmental Biology. "Rather than treating a single disease, there is potentially a treatment for a pathological process shared between many neurodegenerative disorders."

In addition to this viral gene therapy, researchers are studying other possible ways to block SARM1, including small molecules for drug development.