Table 1.
Disorders | Molecular defect | Potential epigenetic targets | Ref. |
---|---|---|---|
NDD | |||
Down syndrome | Trisomy for chromosome 21—results in overexpression of genes leading to abnormal brain development | Goal—Suppress expression from one chromosome 21 | [157] |
• Whole chromosome silencing in trisomic neurons | |||
• Insertion of an inducible X-inactive specific transcript (XIST) into DYRK1A locus in induced pluripotent stem cells from a Down syndrome patient | |||
• XIST-mediated silencing reversed the deficits in neuronal proliferation and neural rosette formation | |||
• Potential novel approach to therapy in Down syndrome | |||
Kabuki syndrome | Mutations in the myeloid/lymphoid or mixed-lineage leukemia 2 (MLL2) gene, a methyltransferase that methylates histone H3 at Lys-4 | Goal—Promote methylation of H3K4 | [144–146] |
• Histone methylating agents or MLL2 mimics | |||
• Histone deacetylase (HDAC) inhibitors have been shown to up-regulate H3K4 methylation | |||
Fragile X syndrome | Expansion of a CGG trinucleotide repeat (>200 triplet) results in hypermethylation of the 5’-untranslated region and the upstream CpG island within the promoter of FMR1 gene resulting in transcriptional repression of the FMR1 gene | Goal—Transcriptional reactivation of FMR1 | [65, 66, 158] |
• DNA demethylation agent 5-azadeoxycytidine | |||
• Histone hyperacetylation agents such as 4-phenylbutyrate, sodium butyrate, and trichostatin A | |||
• Non-epigenetic approaches based on synaptic biology | |||
ASD | |||
Rett syndrome | MeCP2 mutation resulting in loss of MeCP2 function | Goal—Normalize MeCP2 levels | [148, 150] |
• Viral delivery of MeCP2 complementary DNA under native promoter to restore physiological levels of MeCP2 protein | |||
• Insufficient evidence that epigenetic modifiers (HDAC inhibitors or histone acetyltransferase inhibitors) augment MeCP2-mediated function | |||
Angelman syndrome | Mutation or deletion of the maternal UBE3A gene | Goal—Restore UBE3A expression in neurons | [38, 40] |
• Unsilence the imprinted paternal UBE3A allele—topotecan | |||
• Inhibition of paternal UBE3A antisense RNA transcript expression | |||
Prader–Willi syndrome | Mutation in the paternal chromosome 15q11.2–13; loss of expression of paternally-derived genes | • Identifying the epigenetic architecture in this region will help in identifying novel therapeutic targets | [42] |
UBE3A = ubiquitin protein ligase E3A