Epigenome editing, a CRISPR therapy modulating DNA methylation

Proposal for platform construction and development of drugs for rare genetic diseases

Expectations for joint research with companies

  • We would like to collaborate with companies that have platform technologies for (1) mRNA expression, (2) liposomes and (3) viral vectors to achieve efficient expression of constructs in vivo and to build an epigenome-editing therapeutic platform.
  • We also wish to collaborate with pharmaceutical companies and biotech interested in the therapeutic approach of epigenome editing for rare diseases and disease therapeutics

Background and Technology

The link between the epigenome and disease is attracting attention, and DNA methylation inhibitors that induce the expression of cancer-suppressor genes have been approved for the treatment of leukemia. However, there are significant concerns about side effects as demethylation and gene expression are induced not only for a target gene but also for other genes as well. In disease therapies targeting epigenomic regulation, it is desirable to develop control techniques that allow methylation and demethylation to be restricted to specific genes only.

Dr Hatada and colleagues (Gunma University) applied genome editing technology to develop a technique to demethylate only specific genes by expressing dCas9 and methyltransferases in the cells (Fig A, B). Furthermore, they applied this technology to the brain of mouse fetuses and confirmed that it worked effectively. In addition, a mouse that constantly induces demethylation of the H19 gene reproduced the symptoms of Silver-Russell Syndrome (SRS), which is caused by hypomethylation of the H19 gene (Fig C, D).

This technology is expected to be applied to epigenomic therapies such as activation of tumor suppressor genes, incurable diseases caused by epigenetic dysregulation and muscular dystrophy disease treatment by inducing Utrophin expression. At present, the project focuses on the establishment of the basic technology in combination with mRNA expression and delivery technology for application in living organisms.

Data

  • Optimal constructs that are efficiently demethylated when dCas9-SunTag, scFv-TET1 and gRNA are co-expressed in cells (A, B). See ref. Nature biotechnology VOL 34 No.10
  • Transgene-transfected mice that constantly express dCas9-SunTag, scFv-TET1 and gRNA targeting the H19 gene showed hypomethylation of the H19 gene region and presented symptoms of SRS, including reduced birth weight and impaired growth (C, D).

Examples of applications in Rare genetic disorders

Epigenomic diseases (Silver-Russell Syndrome): diseases caused by hypomethylation of the H19 gene (see figure C below) and treated by inducing methylation of the H19 gene.

Haploinsufficiency genetic diseases (e.g., Marfan Syndrome): diseases caused by a lack of transcripts in the Fbn1 gene, which are treated by demethylating the target Fbn1 gene site to improve expression and transcripts.

Dominant genetic diseases (e.g., familial amyloid polyneuropathy): methylation targets the mutant transthyretin gene responsible for amyloid deposition, thereby suppressing its expression. Once methylated, it is maintained after cell division and is expected to have a more sustained effect than siRNA.

Muscular dystrophy: expression of Utrophin, which is inactivated by methylation in muscle cells, is induced by demethylation editing to complement Dystrophin dysfunction by Utrophin expression.

Product No. WL-04254

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