Understanding the Human Genome
The human genome has four types of bases found in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). Adenine pairs with thymine, and cytosine pairs with guanine. The genome is comprised of over three billion of these base pairs in two intertwining strands of DNA; the sequence of these bases encodes genes.
DNA is transcribed into RNA which is translated into protein. Misspellings of even a single letter of a gene, known as point mutations, can yield proteins that are dysfunctional or missing altogether, causing disease.
Base Editing: A new class of precision genetic medicines
Base editors have two principal components that are fused together to form a single protein:
(i) a CRISPR protein, bound to a guide RNA, that leverages the established DNA-targeting ability of CRISPR, but modified such that they do not cause a double-stranded break, and (ii) a base editing enzyme, such as a deaminase, which carries out the desired chemical modification of the target DNA base. This proprietary combination enables the precise targeting and editing of a single base pair of DNA, which has not been previously possible to our knowledge.
When introduced into a cell, the CRISPR targets the desired genomic location by recognizing a complementary section on the DNA to the section encoded in the guide RNA. The deaminase then makes the desired edit to a target base in the editing window.
We believe that the modular and individual components of our base editors can be rapidly customized for specific diseases and create new therapeutic programs. By changing the guide RNA portion of the CRISPR protein, we can quickly and precisely retarget base editors to different genomic locations based on their gene sequences. By changing the deaminase, we can control which base is edited (e.g., C or A).
Advantages in Base Editing
Base editing is an emerging new class of precision genetic medicines creating potential therapeutic options designed to overcome the limitations of existing approaches and expand the potential of genetic medicine. We believe base editors have several advantages over existing gene editing approaches: 1) The creation of precise, predictable and efficient genetic outcomes at a targeted sequence 2) High efficiency editing without need for template-based homology directed repair, and 3) Avoidance of the unwanted consequences of double-stranded DNA breaks, such as frequent insertions and deletions or larger-scale genomic rearrangements.
Treating disease, one letter at a time
By rewriting a single base in the genome, base editors can correct disease-causing point mutations, modify genes to create protective genetic variations, activate gene expression, silence gene expression, or multiplex-edit several sites simultaneously.
Future Horizons in Precision Genetic Medicines
A key part of our strategy is to continue to build on the expertise of our innovative research culture by exploring new and complementary technologies in base editing, gene editing, and genetic medicine.
Beam has exclusively licensed the use of prime editing, an emerging gene editing technology that utilizes a reverse transcriptase to rewrite short sequences of DNA at a CRISPR-directed location, without causing a double-stranded break, from Prime Medicine in certain fields and for certain applications similar to those Beam is already pursuing with base editing. The license gives Beam the exclusive right to make any transition mutation (such as an A-to-G or C-to-T change) as well as to exploit any approach for the treatment of sickle cell disease using prime editing.
Through a license agreement with the Broad Institute of MIT and Harvard, Beam has exclusively licensed the use of certain RNA base editing technology and Cas12b nuclease technology for all applications. Our licensed RNA base editing technologies include the REPAIR™ system for A-to-I editing, as well as the RESCUE™ system for C-to-U editing. RNA base editing may be useful for transient editing of the transcriptome. Access to the Cas12b nuclease technology allows us to create DNA base editors that can bind to different target sites in the genome, further expanding the range of sites that we can edit. Additionally, access to the Cas12b nuclease technology allows us to make “cut” edits, which may be appropriate for some applications that require a double-stranded break.
Collectively, these additional technologies enable us to advance a broad portfolio of programs across a wide range of editing profiles and multiple delivery vehicles, in some cases exploring multiple editing approaches in parallel for our highest priority therapeutic programs.