The science behind Beam

Our groundbreaking CRISPR base editing technology allows us to make permanent, specific edits to single bases in DNA and RNA. Base editor therapeutics represent a new class of “precision genetic medicines,” combining precision targeting of the genome with precision control of editing outcomes.

DNA is made up of four nucleobases, or “bases,” represented by the letters A, C, G, and T. The human genome is made of billions of these bases paired together in two strands – A with T and C with G.

RNA molecules are single-stranded copies of gene sequences that serve as temporary instructions for the assembly of proteins in the cell. Errors in the DNA, called mutations, can then be copied into RNA and later into proteins, causing cellular dysfunction and disease.

Base Editing: A new category in CRISPR gene editing

Base editors have two components: First, we use a CRISPR enzyme, which can be programmed to specifically target any location within the genome. Depending on the choice of CRISPR enzyme, we can target either DNA or RNA. Unlike nuclease editing, base editing enzymes are modified to avoid cutting the DNA or RNA once they bind to the target site.

Instead, an editing enzyme is tethered to the modified CRISPR enzyme and directly converts one base to another. The initial versions of base editors make edits using deaminases, which produce predictable chemical modifications to nucleobases (A-to-G or C-to-T for adenosine or cytidine deaminases, respectively). When targeting DNA, additional components of the technology help influence repair pathways to make the edit permanent. Because the system is modular, selection of different CRISPR enzymes or deaminases produces base editors with different gene targeting and editing capabilities.

DNA base editors have the potential to permanently correct or modify a gene after one-time delivery to the target tissue. RNA base editors can deliver either long-term or transient modifications of protein function based on constitutive or short-term delivery of the editor. In both cases, the final gene sequence expressed by the cell is corrected, creating a functional protein and treating the disease.

Using this technology, we believe we can precisely repair a variety of disease-causing point mutations, write in beneficial genetic variations known to protect against disease, or modulate expression of disease-causing genes.

Because base editing directly converts a base in an existing gene, it is not reliant on importing new DNA sequences. Base editing also occurs in both dividing and non-dividing cells, and the resulting edited gene maintains its normal regulation and expression level. The base editor is designed to minimize the frequency and impact of any “off-target” genetic changes, both within the target gene and elsewhere across the genome.

To create base editor therapeutics, Beam is working with a variety of validated and emerging technologies for delivering base editors to different tissues and cell types.

Treating disease, one letter at a time

Over half of genetic errors driving disease are the result of point mutations – a single-letter change in the billions of As, Ts, Cs, and Gs forming the genome. Changing that one base “back to normal” in enough cells may help us prevent, modify, and even cure serious genetic diseases. In addition, certain natural genetic variations – also often single-base changes in the genome – are known to prevent or ameliorate disease. Using base editors to “write in” such protective changes in the genome may help prevent or treat a wide range of diseases.

Precise, Programmable Changes

Base editors can deliver precise, programmable changes to a target gene sequence, enabling a wide variety of therapeutic strategies.