#AANAM – Gene Therapy Treats CMTX Even After Disease Onsest, Mouse Study Suggests

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Gene therapy can be of benefit even after neuropathy has begun, research in a mouse model of X-linked Charcot-Marie-Tooth disease (CMTX) found.

The study, “Gene therapy after onset of neuropathy provides therapeutic benefit in a model of CMT1X,” was presented by Kleopas Kleopa at the 2019 American Academy of Neurology (AAN) annual meeting that recently concluded in Philadelphia.

CMTX is caused by mutations in the gene GJB1, which encodes for a protein called connexin-32 (Cx32). These mutations cause the loss of a working protein, leading to manifestation of the disease.

An intuitive way to treat CMTX would be to “add” a functional (that is, non-mutated) version of this gene into patients’ cells. Viral gene therapy, which uses a modified virus to deliver a gene to particular kinds of cells, attempts to do just that.

The study’s researchers had previously used this strategy to show therapeutic benefits in a mouse model of CMTX. They constructed a virus to deliver a working version of the gene to Schwann cells of these mice. Of note, Schwann cells produce myelin, the protective coating around neurons that helps them function and that isn’t produced correctly in CMTX.

CMTX mice typically start developing disease features at three months of age. So in the previous study, the researchers gave them with the gene therapy just before this timepoint, or at age 2 months. But in the real world, a disease — especially a rare disease — might not be diagnosed before its symptoms are evident.

So, the research team wondered, might this gene therapy still be of benefit after the start of disease?

The team injected, via the spinal canal, one group of CMTX mice with their Cx32-encoding virus and another with a mock virus not coding for this protein (a control group). These injections were given to the mice at 6 months old, well after disease onset. The researchers then looked at the mice’s behavior and for changes in the their nervous systems at 8 and 10 months old.

Analysis confirmed that mice given the gene therapy expressed the Cx32 protein in the correct cells and body tissues. Treated mice also had less inflammation and more myelin (less abnormally myelinated fibers) than controls, and treated mice had lower levels of neurofilament light (Nfl) — a clinically relevant biomarker of nerve damage — in their blood.

Treated mice also showed improved motor skills and better sciatic nerve conduction velocity, which essentially means that  their neurons “worked better” than those of controls with natural disease progression.

These data suggest that gene therapy can be beneficial in CMTX even if the therapy isn’t started until after the disease has started to progress, the study siad.

“Intrathecal [injection into the spinal canal] gene delivery after the onset of peripheral neuropathy still offers a significant therapeutic benefit in this disease model providing a proof of principle for treating patients with CMT1X,” the researchers concluded.