Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

https://pubmed.ncbi.nlm.nih.gov/32610343/

Pelizaeus-Merzbacher disease (PMD) is a rare type of leukodystrophy caused by mutations in the gene PLP1, which contains the instructions for making a cellular protein known as ‘proteolipid protein’. Mutations in PLP1 can occur in a variety of places in the gene, some are linked to the development of severe and fatal form of PMD, and some are linked to a milder form of the disease. Those mutations linked to more serious forms of the disease include ‘substitutions’ (the swapping of a single subunit of DNA for another, erroneous subunit, and ‘copy variations’ (a multiplication of the number of PLP1 copies in a cell). Unusually, researchers have found that when PLP1 is completely absent, PMD manifests in a much milder form, suggesting that attempting to completely suppress PLP1 function may be a viable therapeutic strategy for PMD patients. The scientists involved in this study demonstrated that when the PLP1 gene was completely and permanently deleted in a mouse ‘model’ of human PMD, both nerve function and lifespan were increased. This type of strategy would, at least currently, not be possible to carry out in humans due to the nature of the genetic engineering involved. However, the researchers found that they could administer a type of chemical which decreases PLP1 expression in mice in a way which is currently feasible to carry out in humans. In these mice, increased nerve function was observed, as well as improved motor and respiratory function and lifespan. Demonstration that this treatment works, at least in mice, is a promising development not only in the field of PMD research, but also other diseases characterised by nerve cell dysfunction. The authors of this study make clear that further preclinical (laboratory) work will be needed to optimise this potential treatment, but results from work so far has been very promising, as only a single dose of the chemical in question can elicit a significant and sustained improvement in the symptoms being experienced by the PMD mice.