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Antisense therapy for MECP2 duplication syndrome

A preclinical study has provided experimental evidence that supports the use of antisense oligonucleotides as a strategy to treat MECP2 duplication syndrome.

MECP2 duplication syndrome

MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males. It arises from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus on the X chromosome. The MECP2 gene is an epigenetic regulator that is crucial for normal brain function. It is a dosage-sensitive protein that is involved in two devastating childhood disorders. MDS being one, and Rett Syndrome (RTT) being the other. While duplications in this gene cause MDS, loss-of-function mutations cause RTT. MDS accounts for ~1% of X-linked cases of intellectual disability. It manifests almost exclusively in males and is also characterised by infantile hypotonia, intellectual disability, anxiety, motor dysfunction, epilepsy, recurrent respiratory tract infections and premature death.

Researchers have found that MDS-like phenotype can be reversed in adult symptomatic mice when the MeCP2 protein concentration is normalised. This can be done genetically or using MECP2-specific antisense oligonucleotides (ASOs) administered into the brain. ASOs are small modified nucleic acids that can selectively hybridise with transcripts from target genes and silence them. ASO treatment for neurological disorders has several advantages, including high target specificity, limited toxicity, extended half-life and precise dosing. However, one challenge of this approach is the fact that the ASO would target both MECP2 alleles. Knocking down of MeCP2 below wild-type levels could cause RTT symptomatology. As a result, in order to consider ASOs as a potential therapy for MDS, researchers must ensure that the ASO dosage can be reliably titrated. 

Antisense therapy

In this study, published in Science Translational Medicine, researchers generated and validated a humanised mouse model of MDS that has two human MECP2 alleles and no mouse allele. Using this model, the team examined the ASO distribution in the brain after an acute injection. They specifically assessed the pharmacodynamics of ASO-mediated MeCP2 downregulation as well as the molecular and behavioural response.

The researchers found that injection of the MECP2-ASO efficiently downregulated MeCP2 expression throughout the brains of these mice. It also mitigated several behavioural deficits and restored expression of selected MeCP2-regulated genes in a dose-dependent manner without any toxicity.

These results show that CNS administration of MECP2-ASO is well tolerated and beneficial in this mouse model. It also provides a translatable approach that could be feasible for treating MDS.

Dr Hude Zoghbi, Professor at Baylor College of Medicine, stated:

“I see a very clear path from these proof-of-concept results to future clinical trials that test the safety and efficacy of MECP2-ASOs in children with MDS. Moreover, our study suggests the antisense strategy could potentially also be used to treat other childhood developmental disorders caused by genetic duplications.”

Image credit: By vectorgraphit – freepik

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