In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing

Sinnamon, John R.; Kim, Susan Y.; Fisk, Jenna R.; Song, Zhen; Nakai, Hiroyuki; Jeng, Sophia; McWeeney, Shannon K.; Mandel, Gail

doi:10.1016/j.celrep.2020.107878

Cited by 54 publications

(47 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There are two main approaches, firstly that of addressing downstream effects of the MECP2 mutation, for instance attempting to upregulate genes under MeCP2’s control, such as BDNF or IGF1 [reviewed in Vashi and Justice (2019) ], or neurotransmitter pathways such as NMDA receptors, or downstream target K + /Cl – co-transporter 2 (KCC2) ( Tang et al, 2019 ). The second approach is to target MECP2 directly, either through gene therapy, delivering a functional version of the MECP2 gene exogenously, for example using adenoviral delivery systems [e.g., ( Tillotson et al, 2017 )], through correcting the mutation at the level of genomic DNA, for example using CRISPR/cas9 editing, or at the RNA level by programmable RNA editing (e.g., Sinnamon et al, 2020 ), or using compounds such as aminoglycosides to enable “read-through” of MECP2 nonsense mutations [e.g., ( Merritt et al, 2020 )].…”

Section: Subsectionsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

View full text Add to dashboard Cite

Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

show abstract

Section: Subsectionsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

View full text Add to dashboard Cite

show abstract

“…The first report on Mecp2 RNA editing was published by the Gail Mandel lab in 2017 where an exogenous, modified ADAR2 and guide was used to successfully edit 72% G to A mutations in RNA from Mecp R106Q mouse neurons (Sinnamon et al, 2017). In 2020 Sinnamon and colleagues successfully edited up to 50% of mRNA in neurons in developing brains of Mecp2 mutant mice using a similar approach (Sinnamon et al, 2020). The potential of RNA editing as a Rett therapy is limited by the fact that although endogenous RNA editing proteins such as ADAR1, exist naturally in the brain, current approaches express a modified RNA editing protein delivered by an AAV virus and the fact that these ADAR2 like proteins primarily edit only G to A mutations (Sinnamon et al, 2017(Sinnamon et al, , 2020.…”

Section: Potential Treatments Under Development For Rett Syndromementioning

confidence: 99%

The Molecular Functions of MeCP2 in Rett Syndrome Pathology

Osman

Yasui

2021

Front. Genet.

View full text Add to dashboard Cite

MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.

show abstract

“…The efficiency of RNA editing can be improved by using chemically modified sgRNA and a next-generation viral delivery vector or nanoparticle. For example, AAV delivery of exogenous RNA editor and guide sequence has enabled in vivo repair of mutant RNAs in mouse models of neurological disease 190 . Compared with gene editing, RNA editing also makes limited kinds of change to RNA.…”

Section: Other Gene Knock-in and Gene Correction Strategiesmentioning

confidence: 99%

CRISPR-based strategies for targeted transgene knock-in and gene correction

Lau

Tin

Suh

2020

Fac Rev

View full text Add to dashboard Cite

The last few years have seen tremendous advances in CRISPR-mediated genome editing. Great efforts have been made to improve the efficiency, specificity, editing window, and targeting scope of CRISPR/Cas9-mediated transgene knock-in and gene correction. In this article, we comprehensively review recent progress in CRISPR-based strategies for targeted transgene knock-in and gene correction in both homology-dependent and homology-independent approaches. We cover homology-directed repair (HDR), synthesis-dependent strand annealing (SDSA), microhomology-mediated end joining (MMEJ), and homology-mediated end joining (HMEJ) pathways for a homology-dependent strategy and alternative DNA repair pathways such as non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR) for a homology-independent strategy. We also discuss base editing and prime editing that enable direct conversion of nucleotides in genomic DNA without damaging the DNA or requiring donor DNA. Notably, we illustrate the key mechanisms and design principles for each strategy, providing design guidelines for multiplex, flexible, scarless gene insertion and replacement at high efficiency and specificity. In addition, we highlight next-generation base editors that provide higher editing efficiency, fewer undesired by-products, and broader targeting scope.

show abstract

In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing

Cited by 54 publications

References 63 publications

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

The Molecular Functions of MeCP2 in Rett Syndrome Pathology

CRISPR-based strategies for targeted transgene knock-in and gene correction

Contact Info

Product

Resources

About