Beam Publishes Data Demonstrating Ability to Rationally Design Base Editors for Precise Editing

Rare Daily Staff

Beam Therapeutics, in a new publication of its work, describes a new type of gene editing known as inlaid base editors, architectural variants of base editors that have attributes of enhanced specificity and altered activity windows relative to foundational base editors.

Rather than just removing a piece of DNA, base editors are used to convert a specific DNA base at a specific location. The work, published in The CRISPR Journal, highlights Beam’s application of its inlaid base editors for BEAM-102, one of its base editing programs in development for the treatment of sickle cell disease (SCD).

“Direct correction of the sickle-causing mutation with traditional gene editing technologies has been limited by low efficiency,” said Giuseppe Ciaramella, president and chief scientific officer of Beam. “The therapeutic potential of our rationally designed IBEs is exciting. Not only have these differentiated base editors demonstrated the potential to efficiently convert the disease-causing sickle hemoglobin allele into a normal variant; they open the doors to potentially target a broad range of other genetic diseases.”

Beam’s base editors use a DNA-targeted deaminase to create a precise chemical modification of a target DNA base with high precision and limited off-target consequences. IBEs expand the breadth of potential base editing targets by extending the range of editing windows that can be created for any given CRISPR-Cas protein used to target the DNA. By inserting the deaminase into the CRISPR protein at various strategic positions, repositioning the deaminase’s active site, IBEs enable editing outside the traditional editing window. The broad modularity of these proprietary base editor designs was demonstrated using both the adenine base editor and the cytosine base editor.

Sickle cell disease (SCD) is a lifelong, inherited blood disorder in which red blood cells are abnormally shaped in a crescent, or “sickle” shape, which restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. It is also characterized by severe and chronic inflammation that worsens vaso-occlusive crises during which patients experience episodes of extreme pain and organ damage.

BEAM-102 aims to treat SCD by directly editing the causative sickle hemoglobin point mutation to recreate a naturally occurring normal human hemoglobin variant. The variant has been reported to have the same function as the wild-type allele and does not cause SCD. Findings in the paper show that Beam’s inlaid base editors resulted in highly efficient editing levels of more than 70 percent in CD34+ cells from both sickle trait and sickle cell disease individuals. Additionally, the IBE demonstrated significantly reduced guide-independent off-target editing in vitro.

The company said it plans to submit to regulators the first application to begin human clinical trials for a base editor program in the second half of 2021.

Photo: Giuseppe Ciaramella, president and chief scientific officer of Beam