Pelizaeus–Merzbacher Disease (PMD) is an inherited leukodystrophy affecting the central nervous system (CNS)—a rare disorder that especially concerns males. Its estimated prevalence is 1.45–1.9 per 100,000 individuals in the general population. Patients affected by PMD exhibit a drastic reduction or absence of myelin sheaths in the white matter areas of the CNS. The Proteolipid Protein 1 (PLP1) gene encodes a transmembrane proteolipid protein. PLP1 is the major protein of myelin, and it plays a key role in the compaction, stabilization, and maintenance of myelin sheaths. Its function is predominant in oligodendrocyte development and axonal survival. Mutations in the PLP1 gene cause the development of a wide continuum spectrum of leukopathies from the most severe form of PMD for whom patients exhibit severe CNS hypomyelination to the relatively mild late-onset type 2 spastic paraplegia, leading to the concept of PLP1-related disorders. The genetic diversity and the biochemical complexity, along with other aspects of PMD, are discussed to reveal the obstacles that hinder the development of treatments. This review aims to provide a clinical and mechanistic overview of this spectrum of rare diseases.

Depuis leur découverte à la fin des années 1990, les siRNA (small interfering RNA) ont suscité l’intérêt des chercheurs et des compagnies pharmaceutiques pour le développement de thérapies ciblées. Cependant, leur application thérapeutique fait face à plusieurs obstacles dans les milieux biologiques dues à leur demi-vie plasmatique courte et leur hydrophilie. D’où la nécessité de les protéger de la dégradation. Cette thèse a pour but de tester des formulations pour délivrer les siRNA au système nerveux central (SNC) en vue de futures applications thérapeutiques.