POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

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.

Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation

“…Oligodendrocytes are myelin-forming cells of the CNS. During myelin development or remyelination, oligodendrocytes need to produce large amounts of proteins to mature, and disruption of tRNA transcription can cause dysregulation of global protein translation during the critical phase of myelin development, ultimately leading to abnormal myelin formation 5 , 24 . The second hypothesis suggests that reduced Pol III function can lead to reduced levels of specific Pol III transcripts involved in transcription, RNA processing, and translation, thus affecting the development and function of oligodendrocytes and/or neurons 23 .…”

“…POLR3A encodes the largest subunit of Pol III, which together with POLR3B forms the catalytic center of the enzyme. Pol III is involved in the transcription of a variety of small molecules of non-coding RNAs (NC-RNAs), including transfer RNAs (tRNAs), 5S ribosomal RNA (rRNA), 7SL and 7SK RNAs, and U6 small nuclear RNA 5 . Most Pol III transcripts are involved in the regulation of essential processes such as transcriptional regulation, RNA processing, and protein translation 6 , and the normal function of Pol III plays a key role in the maintenance and development of myelin 7 .…”

Progress in leukodystrophies with zebrafish

“…4H leukodystrophy (OMIM #614381) is characterized by the clinical features of hypomyelination, hypodontia, and hypogonadotropic hypogonadism (Perrier et al, 2021). It is caused by mutations in any of the POLR1C , POLR3A , POLR3B , and POLR3K genes, which encode the subunits of an enzyme called RNA polymerase III.…”

RNA Polymerase III Subunit Mutations in Genetic Diseases

“…To this date, no curative treatment is available and supportive care is the standard. Understanding the pathophysiology of these diseases will be key in order to develop therapies that can be tested in the pre-clinical setting and eventually translated to the clinic (Perrier et al, 2020b). Specifically, it remains enigmatic how mutations in a ubiquitously expressed and essential enzyme such as Pol III lead to disorders with clinical features that are largely restricted to the CNS and a few other tissues, all of which originate from neural crest cells.…”