Genome Regulation: ZF-transcription factors for CNS disorders

Sangamo’s zinc fingers (ZF) can be coupled to transcription factor domains to potentially create genomic medicines that regulate gene expression directly or through epigenetic mechanisms.

Overview

ZF-transcription factors can fine-tune gene expression based on the genetic needs of each disease.

They can be designed to:
  • Reduce the expression of a pathogenic gene
  • Selectively repress expression of a mutant allele while allowing for the expression of the healthy allele
  • Activate the expression of genes that are inadequately expressed

We can engineer ZF-transcription factors with the right potency to allow us to achieve precise levels of gene expression in the brain.

For example, in tauopathies such as Alzheimer’s disease, we target reduction of tau at the DNA level to reduce and prevent accumulation of toxic protein aggregates that are part of the disease pathology.

For some diseases such as ALS, a disease-causing defect is only in one copy of the gene (one allele).

ZF-transcription factors are incredibly specific and can be designed to selectively repress only the disease allele, while sparing expression of the healthy copy.

Overall, ZF-transcription factors offer the potential to create lasting cures for debilitating neurological diseases.

CNS Delivery

Delivery to the central nervous system (CNS) is a major hurdle for clinical applications of genomic medicine, as the blood–brain barrier (BBB) limits the brain distribution of virtually all intravenously administered macromolecules. Sangamo’s SIFTER™ platform (Selecting In vivo For Transduction and Expression of RNA) allows us to engineer adeno-associated virus (AAV) capsids with potentially improved CNS transduction efficiency, as we aim to enable therapeutic application of genomic medicines.

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