Sangamo and Astellas Announce Capsid License Agreement to Deliver Genomic Medicine for Neurological Diseases

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Zinc Finger Platform

Sangamo’s zinc finger platform uniquely confers several advantages for genomic medicine, including high resolution genomic design, tunable specificity, and the biotech industry’s most compact DNA binders for efficient cellular delivery.

Zinc finger proteins are natural human proteins

Zinc finger proteins (ZFPs) are naturally occurring proteins in humans which can recognize and bind to specific DNA sequences. Their natural function is to activate or repress the expression of human genes by turning them on or off. Using natural human proteins is expected to offer better safety compared to technologies derived from non-human sources.

We can engineer ZFPs to recognize any unique DNA sequence of our choosing. Our modular approach usually involves using four to six zinc fingers, each of which can recognize a short DNA sequence. We can link multiple fingers together to form a zinc finger array that can recognize longer stretches of DNA, thus improving specificity.

We then attach the zinc finger array to a functional domain which imparts a change to the targeted DNA sequence, such as editing, repressing, or activating a gene.

Zinc Finger Proteins are natural human proteins

Zinc finger technologies are versatile and customizable

Our zinc finger technologies, which are composed of a DNA-binding zinc finger array and a functional domain, are highly versatile and customizable. We can append a variety of different functional domains, allowing us to adapt and optimize the functionality based upon the specific disease of interest.

Preclinical & Clinical Development

Genome regulation with zinc finger transcriptional regulators

Our most advanced preclinical zinc finger programs use zinc finger transcriptional regulators (ZF-TRs), which aim to epigenetically regulate the expression of a target gene. They comprise zinc finger repressors (ZFRs) and zinc finger activators (ZFAs):

  • ZFRs can be created by attaching a zinc finger array to a repression domain to down-regulate or completely turn off a gene. This decreases the expression of a target gene relative to an untreated cell.
  • ZFAs are obtained by attaching a zinc finger array to an activation domain. This increases the expression of a target gene relative to an untreated cell.

We are evaluating ZFRs and ZFAs as potential treatments for several neurological disorders, such as chronic neuropathic pain, prion disease and Huntington’s disease.

ZF-Regulation_steps_Feb2023-web

Making precise DNA changes with zinc finger base editors

Base editing works by changing individual nucleotides, the building blocks of DNA, from one base to another (e.g., changing a “C” base into an “A” base). Base editing allows to make precise changes to DNA without cutting the DNA strand, thus reducing the risk of errors.

Sangamo’s scientists developed a compact base editor system that can be targeted with high precision and specificity using zinc fingers. The total size of this ZF base editing system is compatible with known upper limits for state-of-the-art viral vectors.

Learn more about our base editing platform

Zinc finger base editing architecture

Zinc finger genome editing

Zinc fingers can also be attached to a nuclease, an enzyme that cuts DNA. This creates a zinc finger nuclease (ZFN) which can be used to introduce a cut at a predefined location in the DNA sequence. The natural DNA repair process within the cell then takes over. This process can be harnessed to achieve several outcomes that may be therapeutically useful.

For example, ZFNs can be used to disrupt genes (this is called “knocking out” the gene function). We notably use ZFNs to disrupt certain genes to develop allogeneic cell therapies for autoimmune diseases and cancer. We can also use ZFNs to knock out genes involved in disease pathology. We have also used ZFN-mediated genome editing of the BCL11A erythroid-specific enhancer in hematopoietic stem progenitor cells as a potential treatment for Sickle Cell Disease.

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