Charcot-Marie-Tooth disease (CMT) is the name given to a group of inherited disorders of the peripheral nervous system. CMT1 is the most common form of CMT and accounts for two-thirds of all cases. CMT subtype 1A (CMT1A) is the most common subtype of CMT1, accounting for 60 percent of CMT1 cases.
There is currently no cure for CMT; treatments focus on the management of symptoms to improve patients’ quality of life. PMP22 antisense oligonucleotides (ASOs) is an experimental treatment that is in a preclinical stage of development.
How PMP22 antisense oligonucleotides work
People with CMT1A produce too much of a protein called PMP22. PMP22 is an essential component of myelin, the insulating material that prevents the loss of electrical signals as they travel along nerve fibers. Too much PMP22 protein cannot be processed correctly and results in a lack of functional protein.
The overproduction of PMP22 is caused by a duplication (an extra copy) of the PMP22 gene that provides instructions to build the protein.
PMP22 messenger RNA (mRNA) serves as a messenger between the PMP22 gene and PMP22 protein. mRNA is produced in the cell nucleus, where the genetic information is stored, then travels outside the nucleus, where proteins are made. PMP22 ASOs are single-strand synthetic nucleic acid molecules (the same material of which RNA is made) that bind to PMP22 mRNA. This marks the PMP22 mRNA for degradation so no PMP22 protein is made. The idea is to deliver PMP22 ASOs in such an amount that healthy levels of PMP22 protein are produced — enough to build functional myelin — but below levels that would interfere with protein processing.
Studies with PMP22 antisense oligonucleotides
PMP22 ASOs have not been tested in human clinical trials; research is currently at the stage of animal studies.
The animals received weekly injections of PMP22 ASOs for nine weeks. The ASOs treatment resulted in a reduction of PMP22 protein and myelination, and nerve cell function reached almost the same levels as in healthy wild-type animals. The PMP22 mRNA levels also decreased in the skin, suggesting that skin biopsies might be a useful way in future clinical trials to assess whether the therapy successfully reduces PMP22 levels.
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