Category: Pelizaeus-Merzbacher disease (PMD)

The goal of this project is to further develop and optimize a gene therapy protocol for Pelizaeus‐ Merzbacher‐like disease 1 (PMLD1). This disorder is caused by mutations affecting an important protein in oligodendrocytes, connexin47, which forms most of their direct communication channels with other cells in the brain, also called gap junctions. Connexin47 is found only in oligodendrocytes but not in other brain cells. Since oligodendrocytes are responsible for forming the myelin in the brain, their impairment caused by loss of connexin47 leads to inadequate formation of myelin early on during development, and to further destruction and degeneration of as the disease progresses. Previous studies in cultured cells and in experimental mouse models of the disease confirmed that loss of connexin47 function specifically in oligodendrocytes causes the disease. Therefore, in previous project funded by ELA, we developed a gene therapy approach to deliver the connexin47 gene to oligodendrocytes of mice that lack gap junction channels in these cells. These animals represent a relevant model of the human disease and present many of the characteristic pathological changes. We used an adeno‐associated viral (AAV) vector AAV1/2 serotype based on previous work showing that it targets efficiently oligodendrocytes. We injected the vector into mouse brain to deliver the connexin47 gene at the age of 10 days. We confirmed selective expression in oligodendrocytes and improvement of the brain pathology. In further preliminary studies we also tested intravenously delivered AAV9 vector (currently used in clinical treatments for other diseases) with positive results, but the intravenous approach would not be useful for PMLD1 patients beyond infancy due to limited penetration into the brain.