Allele-selective epigenetic silencing for repeat expansion disorders
DiscO editing platform offers allele-selective epigenetic silencing of disease-associated repeat expansion genes. Utilizing engineered IscB fused with silencing domains, it targets CAG and CTG repeats in Huntington’s disease and myotonic dystrophy type 1.
Overview
The discO editing platform presents a groundbreaking approach for allele-selective epigenetic silencing of disease-associated repeat expansion genes. This innovative technology utilizes a catalytically dead IscB, a Cas9 ancestor, fused with transcriptional silencing and methyltransferase domains to specifically target and silence mutant alleles. Packaged into AAV vectors, this platform is engineered to target CAG and CTG repeat expansions, offering potential therapeutic applications for disorders like Huntington’s disease (HD) and myotonic dystrophy type 1 (DM1). By selectively silencing mutant alleles while preserving normal gene expression, this technology holds promise for treating a broad range of repeat expansion disorders.
Technical specifications
- Utilizes catalytically dead IscB fused to KRAB and methylase domains for targeted gene silencing
- Packaged into AAV vectors for delivery to specific genomic loci
- Designed to target CAG repeats in HD and CTG repeats in DM1
- Testing involves transfecting HEK 293T cells and patient-derived fibroblasts/iPSCs
- Assessment through flow cytometry, RT-qPCR, and nanopore DNA-seq to confirm methylation and gene expression silencing
Technology readiness level
Currently at Technology Readiness Level 3, this platform has demonstrated targeted methylation in model systems and is undergoing further validation in patient-derived cells to assess its efficacy and potential for clinical applications.
About Wake Forest Baptist Medical Center
Atrium Health Wake Forest Baptist Medical Center is a leading academic medical center anchored by Wake Forest University School of Medicine, with a multi-hospital system serving the Piedmont Triad and beyond, and is home to an NCI-designated comprehensive cancer center. Co-located clinical and research facilities speed bedside-to-bench collaboration, and the downtown Innovation Quarter offers labs and offices that embed industry alongside faculty. Through its integration with Atrium Health, the enterprise streamlines contracting and enables multi-site clinical trials across the Carolinas. Research is supported primarily by NIH, with additional competitive federal funding. A dedicated commercialization group, Wake Forest Innovations, manages IP, licensing, and industry partnerships.
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