Beam’s New CRISPR Base Editing Tool Targets Sickle Cell Mutation

Beam Therapeutics has recently unveiled a new CRISPR base editing tool to target sickle cell mutations, a promising approach that holds substantial clinical value for patients with these blood disorders. Sickle cell disease (SCD) is a group of inherited blood disorders caused by a mutation in the hemoglobin-Beta gene that can sometimes be difficult to manage. 

The company announced yesterday the publication of research in The CRISPR Journal describing inlaid base editors (IBEs), which are architectural variants of base editors that “enhance editing efficiency and capability” compared with foundational base editors. In the research, Beam applied its IBEs to the company’s base editing program in development for SCD. 

The adenine base editor tool, known as BEAM-102, was designed to treat SCD by directly editing the causative sickle hemoglobin (HbS) point mutation. In doing so, the tools can recreate HbG-Makassar, which is commonly known as a naturally occurring normal hemoglobin variant. Previous research shows the Makassar variant features the same function as wild-type (HbA) allele and has no causative role in SCD. 

Back in 2017, Beam entered the genome editing space with a platform designed with base editing in mind. 

Base editing, a genome editing technique that modifies a single base at a time, has specific challenges that need to be resolved before it can be used for genetic engineering. Access to particular sites in the genome, for instance, represents a potential limitation to base editing, as this access typically depends on the location of the protospacer adjacent motif sequence. Beam navigated around this limitation via embedding the TadA deaminase inside, thereby creating a novel base editor class called IBEs.

In the recent paper, Beam’s IBE led to highly efficient editing levels of more than 70% in CD34+ cells obtained from patients with the sickle trait (HbAS) and sickle cell disease (HbSS). The studied IBE also led to significantly reduced in vitro guide-independent off-target editing.

“Beam is a pioneer in the field of base editing, and this work is a testament to the leadership of our team of scientists in expanding the role that base editing medicines can play in the treatment of a wide variety of diseases,” according to a statement made by Beam’s President and Chief Scientific Officer, Giuseppe Ciaramella, Ph.D. “Direct correction of the sickle-causing mutation with traditional gene editing technologies has been limited by low efficiency.”

Dr. Ciaramella further explained that rationally designed IBEs hold “exciting” therapeutic potential, particularly in their ability “to efficiently convert the disease-causing sickle hemoglobin allele into a normal variant.” According to Dr. Ciaramella, the findings may lead the way in targeting a broad range of other genetic diseases.

The company’s base editors rely on a DNA-targeted deaminase to facilitate the creation of a specific chemical change of a target DNA base. “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,” the company said in a statement. Through the insertion of the deaminase into a CRISPR protein at different strategic positions, researchers were able to reposition the active site of the deaminase, making IBEs capable of “editing outside the traditional editing window.” 

“With the development of our IBEs, we have once again set a precedent for the expansion and advancement of base editing as a new generation of gene editing technology,” said Beam’s Chief Executive Officer, John Evans, in a statement. “In addition, the patent applications on this work complement and extend Beam’s comprehensive patent portfolio in the field of base editing.”

In a statement about the CRISPR editing tool, Beam noted that it plans to submit the first Investigational New Drug application for its base editor program sometime in the second half of this year.