Our Science: Overview

Targeted Integration: The Next Revolution of Gene Editing

Graphite Bio stands apart in the field of gene editing through its ability to use proprietary CRISPR technology to achieve high efficiency, targeted gene integration that addresses the underlying causes of diseases. Our targeted approach precisely replaces defective genes at their native chromosomal location, allowing for the production of normal gene expression within the inserted cells, potentially avoiding the safety issues associated with first generation gene editing approaches, gene knock-out technologies, and single base gene editing. This novel approach holds broad potential in applications well beyond genetic diseases – including cancer, autoimmune and neurodegenerative diseases – by engineering disease-fighting functions into a variety of cell types.

Highly differentiated, targeted gene integration platform

Graphite Bio’s targeted gene integration platform repairs genetic defects at their source by combining exquisite targeting of the gene replacement machinery to genomic locations with DNA mutations, along with a DNA donor template that harnesses a cell’s own innate DNA repair mechanism called homology directed repair (HDR). The Graphite Bio technology platform works similar to a computer’s “find” and “replace” functions: CRISPR nuclease precisely “finds” the mutated DNA in the defective gene or targeted location and the HDR process, utilizing the Graphite Bio DNA template, then “replaces” in the new DNA to correct the defect or insert a new gene.

Unleashing the full potential of stem cells to cure disease

Initially, Graphite Bio is focused on correcting genetic defects and replacing genes within hematopoietic stem cells (HSCs), which are the somatic stem cells that give rise to all blood and immune cells for the lifetime of an individual. The self-renewing HSCs are corrected ex vivo and reinfused into patients, at which point they are able to differentiate into the appropriate blood and immune cells with restored function – providing the promise of long-term disease remissions and even cures.

Genetic repair of HSCs for use as therapeutics is a complex process that requires, in addition to exquisitely precise DNA repair technology, extremely efficient and reproducible methodologies for patient HSC isolation, engineering and manufacturing to the scale and quality required for clinical use. In addition to optimized DNA “find” and “replace” repair functions, our platform contains key solutions for the challenging process of editing HSCs – which have been historically difficult to achieve high rates of HDR – and ensuring efficient incorporation of repaired genes into the genome. Using our platform, we have been to increase HDR up to 70% efficiency, harnessing our vast scientific expertise in the optimization of this process.

Correcting the underlying cause of sickle cell disease

Our first clinical candidate is for sickle cell disease (SCD) and is anticipated to enter clinical testing in 2021. SCD is a group of rare inherited blood disorders and among the most prevalent monogenic diseases. It is caused by a single mutation in the ß globin gene that leads to misshapen red blood cells resulting in anemia, blood flow blockages, intense pain, increased risk of stroke and organ damage and reduced life span. Sickle cell patients have a 30-year reduced life expectancy – highlighting the need for curative options. There are no approved therapies available that improve survival or have an impact on organ function. Gene correction with a fully functioning adult ß globin gene represents the optimal approach to meeting the challenge in SCD to genetically correct the sickle globin gene mutation.

In the first application of its gene integration platform in SCD, Graphite Bio is optimizing the targeting of the gene editing machinery (Cas9-gRNA) complex to the cell utilizing a non-viral approach. The delivery of the replacement DNA template utilizes an adeno-associated virus 6 (AAV6) vector, a delivery route determined to be particularly effective for hematopoietic cells that has a proven clinical safety profile.

Graphite Bio is advancing a potentially curative investigational genetic therapy in clinical development for SCD that aims to fully correct the underlying disease-causing mutation and lead to the production of completely normal red blood cells with normal adult hemoglobin.