Abstract
Leukodystrophies are a class of rare inherited central nervous system (CNS) disorders that affect the white matter of the brain, typically leading to progressive neurodegeneration and early death. Hypomyelinating leukodystrophies are characterized by the abnormal formation of the myelin sheath during development. POLR3-related or 4H (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) leukodystrophy is one of the most common types of hypomyelinating leukodystrophy for which no curative treatment or disease-modifying therapy is available. This review aims to describe potential therapies that could be further studied for effectiveness in pre-clinical studies, for an eventual translation to the clinic to treat the neurological manifestations associated with POLR3-related leukodystrophy. Here, we discuss the therapeutic approaches that have shown promise in other leukodystrophies, as well as other genetic diseases, and consider their use in treating POLR3-related leukodystrophy. More specifically, we explore the approaches of using stem cell transplantation, gene replacement therapy, and gene editing as potential treatment options, and discuss their possible benefits and limitations as future therapeutic directions.
Highlights
Leukodystrophies are a class of heterogeneous inherited neurological diseases characterized by the predominant impairment of the central nervous system (CNS) white matter, with specific involvement of glial cells (Vanderver et al, 2015; Van Der Knaap and Bugiani, 2017)
Several studies involving the transplantation of human glial lineagespecific cells into shiverer mice show consistent results, with evidence of robust remyelination, prolonged survival, and phenotypic rescue (Windrem et al, 2004, 2008, 2014, 2020; Izrael et al, 2007; Mariani et al, 2019). These results provide support for clinical exploration of this treatment, revealing that glial progenitor cell (GPC) have a migratory potential and can effectively differentiate in vivo when transplanted into another host
The initial preclinical data for this study suggested that intracerebral delivery of AAVrh.10-ARSA was superior to AAV5 both in terms of the overall impact on the model disease and its ability to transduce oligodendrocytes (Sevin et al, 2006, 2007; Piguet et al, 2012), which led to further safety and feasibility assessments in non-human primates leading up to the clinical trial (Zerah et al, 2015)
Summary
Leukodystrophies are a class of heterogeneous inherited neurological diseases characterized by the predominant impairment of the central nervous system (CNS) white matter, with specific involvement of glial cells (Vanderver et al, 2015; Van Der Knaap and Bugiani, 2017). Leukodystrophies affect approximately one in 7,500 individuals, there are many different subtypes with varying individual incidence rates (Bonkowsky et al, 2010; Parikh et al, 2015; Adang et al, 2017). Some leukodystrophies have successful restorative treatments if started early following diagnosis [i.e., pre-or early symptomatic stages (Krivit et al, 1999; Krivit, 2004; Van Den Broek et al, 2018)], most treatments address specific clinical features, providing supportive care (Adang et al, 2017)
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