Promising therapeutic aspects in human genetic imprinting disorders

(2022) 14:146 Chao et al. Clinical Epigenetics https://doi.org/10.1186/s13148-022-01369-6 Open Access REVIEW Promising therapeutic aspects in human genetic imprinting disorders Yunqi Chao1, Yifang Qin1, Xinyi Zou2, Xiangzhi Wang1, Chenxi Hu1, Fangling Xia1 and Chaochun Zou1*    Abstract Genomic imprinting is an epigenetic phenomenon of monoallelic gene expression pattern depending on parental origin. In humans, congenital imprinting disruptions resulting from genetic or epigenetic mechanisms can cause a group of diseases known as genetic imprinting disorders (IDs). Genetic IDs involve several distinct syndromes sharing homologies in terms of genetic etiologies and phenotypic features. However, the molecular pathogenesis of genetic IDs is complex and remains largely uncharacterized, resulting in a lack of effective therapeutic approaches for patients. In this review, we begin with an overview of the genomic and epigenomic molecular basis of human genetic IDs. Notably, we address ethical aspects as a priority of employing emerging techniques for therapeutic applications in human IDs. With a particular focus, we delineate the current field of emerging therapeutics for genetic IDs. We briefly summarize novel symptomatic drugs and highlight the key milestones of new techniques and therapeutic programs as they stand today which can offer highly promising disease-modifying interventions for genetic IDs accompanied by various challenges. Keywords: Genetic imprinting disorders, Genomic imprinting, Therapy, Epigenetic therapy Background In mammals, the term genomic imprinting is an epigenetic phenomenon that, in some autosomal genes, gene expression depends on the parent-of-origin so that only one gene copy from the two parental alleles is preferentially active, either maternally or paternally [1]. In humans, there are approximately 150 imprinted genes residing on chromosomes 6, 7, 11, 14, 15, and 20 [2]. The realization has emerged that imprinted genes can function as pivotal regulators in prenatal and postnatal growth and development control, brain function, body composition, and energy homeostasis [3]. Disturbances in gene dosage, epigenetic regulation, and genomic sequences of imprinted genes may result in their function *Correspondence: 1 Department of Endocrinology, The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, Zhejiang, China Full list of author information is available at the end of the article loss and can cause pathological conditions in humans— imprinting disorders (IDs). Genetic IDs are a subset of congenital diseases caused by common molecular disturbances in genomic imprinting. Since the first human ID—Prader–Willi syndrome (PWS)—was identified in 1989 [4], there have been several other genetic IDs recognized according to genotype–phenotype studies: Angelman syndrome (AS), Beckwith–Wiedemann syndrome (BWS), Silver–Russell syndrome (SRS), pseudohypoparathyroidism types 1a (PHP1a) and 1b (PHP1b), transient neonatal diabetes mellitus (TNDM), Temple syndrome (TS14), Kagami– Ogata syndrome (KOS14), and Schaaf–Yang syndrome (SYS). Currently, there is no dedicated and radical therapy for patients with genetic IDs, and all available first-line therapies per se are mainly supportive of the management and mitigation of partial existing symptoms. These symptomatic treatments usually cannot offer completely satisfactory symptom resolution for ID patients and have limited benefits to improve their quality of life. In the past © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chao et al. Clinical Epigenetics (2022) 14:146 decades, there has been a broad consensus on developing novel symptomatic drugs as candidate pharmacological approaches for genetic IDs. The pharmacotherapeutic armamentariums in progress, aiming at different pathophysiological pathways of every ID, hold great potential to optimize or renew present combinatorial therapies for treating certain symptom domains for ID patients. Moreover, a great interest has been sparked regarding a subset of new and improved techniques and therapeutic programs that, as disease-modifying interventions, could render higher future potentials for treating genetic IDs. These therapies are developed based on the strategies of genetic precision medicine, which mainly target correcting or counteracting the defects caused by the function loss of associated imprinted genes: (1) gene replacement; (2) molecular reinstatement of the normal expression of candidate imprinted genes; (3) silencing the related inhibitory transcripts of imprinted genes, such as clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated endonuclease (Cas) (CRISPR–Cas)-mediated gene editing; and (4) epigenetic circuit reprogramming. These therapies could represent relatively superior and more promising opportunities for managing genetic IDs. However, the majority of these novel therapeutic methods are still at the initial discovery level; therefore, further studies are needed to not only unveil detailed imprinting mechanisms from genetics and epigenetics backdrops but also perform more preclinical and clinical trials on these new interventions. In this review, we summarize recent findings on novel symptomatic drugs for IDs and highlight the advances in the fields of innovative promising therapeutic techniques and treatment programs in progress. The genomic and epigenomic basis of imprinting Imprinted genes can be marked by different epigenetic machinery including DNA methylation, histone modifications, and chromatin structure. These modifications are set up during germline development and can be maintained as the memory of germline-derived parentalspecific origin after fertilization, eluding genome-wide reprogramming [5]. Imprinted genes display the allelic parental expression pattern ubiquitously and permanently in nearly all cell types; however, some imprinted Page 2 of 19 (...truncated)