Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

Abstract

Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models.

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

“…In this study, we solely explored the treatability of the KMT2-associated disorders using ASO-based approaches; however, the use of ASOs is not the only possible therapeutic option for the KMT2-associated disorders, and other genetic strategies can be considered. For example, small-activating RNAs (saRNAs) have been proposed as a future therapeutic application for these histone-methyltransferase-associated NDDs to obtain target gene upregulation [88].…”

“…No disease-modifying, genetic treatments are yet available for any of the KMT2-associated disorders, and most therapeutic strategies focus on managing clinical manifestations and preventing secondary complications [32,34,40,85]. Yet, based on the clinical presentation, the KMT2-associated NDDs can potentially benefit from ASO approaches, which has already been suggested by others [86][87][88].…”

The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect

“…The class of ASOs representing a burgeoning frontier in molecular biology studies is the saRNAs [ 105 ]. Their superior ability for the precise modulation of gene expression through targeted activation of specific genes at the site of promoter structures makes them ideally suited for therapeutic applications for neurodevelopmental disorders [ 106 ], cancer treatment [ 107 ], and diabetes [ 108 ]. Acting as short double-stranded RNA fragments, they are processed by the same RISC complex as siRNAs ( Figure 2 ) [ 109 ].…”