Realizing the full potential of gene editing

Harnessing the power of precise DNA repair

Our UltraHDR™ platform is a novel gene-editing technology designed to allow us to move CRISPR-based gene editing beyond cutting and gene disruption towards precise DNA repair, also known as homology directed repair (HDR). With our platform, we seek to harness the power of the cell’s natural DNA repair processes at high efficiencies to restore function to mutated genes that cause disease. This proprietary technology has the potential to go beyond personalized medicine and deliver individualized therapies with the ability to cure a patient of their genetic disease.

We are initially focused on developing one-time, stem cell-based cures for serious genetic diseases, like sickle cell disease and beta-thalassemia. However, our novel gene editing platform has been observed to be highly efficient across a wide range of cell types, yielding broad potential to treat cancer, autoimmune diseases, and neurodegenerative diseases.

Our UltraHDR™ platform: A ‘find and replace’ approach to gene editing

  1. Find the mutated gene

    First, we identify the genetic mutation that causes a specific disease, just like an editing software would find a misspelled word or incorrect sentence.

  2. Cut the incorrect DNA sequence

    Then, we use our proprietary HiFi Cas9, bound by a guide RNA, to make a highly precise cut to remove the incorrect DNA sequence in the disease-causing gene. Our HiFi Cas9 is specifically engineered to have higher fidelity, leading to more efficient and precise cutting at the target site.

  3. Replace with the correct DNA sequence

    Finally, we deliver a template containing the correct DNA sequence, aiming to restore and normalize function in the disease-causing gene, effectively rewriting a patient’s DNA so they can write the next chapter in their life story.

Our ‘find and replace’ approach to gene editing allows us to correct, replace, and insert genes anywhere in the genome.

Gene correction

Correct point mutations or short DNA stretches in endogenous locus.

Gene replacement

Replace gene driven by own promoter.

Targeted gene insertion

Knock-in promoter gene expression cassette into safe harbor location.

The science behind our gene editing platform

See how we’re using our UltraHDR™ platform to develop what we believe may be a definitive cure for sickle cell disease, and how this same approach is being used to develop potential cures for other diseases thought to be incurable.

Publications

Our vision is a future where the word ‘incurable’ no longer exists—transforming our founders’ groundbreaking discoveries into potential cures. Graphite Bio’s scientific approach is supported by extensive peer-reviewed preclinical research. Explore select publications featuring our novel UltraHDR™ platform below.

Sickle Cell Disease (SCD)

CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Dever DP, Bak RO, Reinisch A, et al. Nature. 2016
Sickle Cell Disease (SCD)

CRISPR/Cas9 genome editing in human hematopoietic stem cells. Bak RO, Dever DP, Porteus MH. Nat Protoc. 2018
Sickle Cell Disease (SCD)

A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Vakulskas CA, Dever DP, Rettig GR, et al. Nat Med. 2018
Sickle Cell Disease (SCD)

Cas9-AAV6 gene correction of beta-globin in autologous HSCs improves sickle cell disease erythropoiesis in mice. Wilkinson AC, Dever DP, Baik R, et al. Nat Commun. 2021
Sickle Cell Disease (SCD)

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. Lattanzi A, Camarena J, Lahiri P, et al. Sci Transl Med. 2021
Sickle Cell Disease (SCD)

CEDAR Trial in Progress: A First-in-Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD. Kanter J, DiPersio J, Leavey P, et al. Presented at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition 2021
Sickle Cell Disease (SCD)

Single-Cell RNA Sequencing of Sickle Cell Reticulocytes to Identify Beta-Globin Genotypes and Associated Gene Expression Differences. Presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition 2022.
Beta-Thalassemia

Development of a Beta-globin Gene Replacement Strategy as a Therapeutic Approach for β-Thalassemia. Wienert B, Wallace K, Bandoro C, et al. Presented at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting 2022
Other Platform Applications

Gene correction for SCID-X1 in long-term hematopoietic stem cells. Pavel-Dinu M, Wiebking V, Dejene BT, et al. Nat Commun. 2019
Other Platform Applications

Engineering monocyte/macrophage-specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing. Scharenberg SG, Poletto E, Lucot KL, et al. Nat Commun. 2020
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Our pursuit of ‘one dose, one cure’

We’re striving to create a future where the word ‘incurable’ no longer exists. The potential cures we’re developing are just the beginning of our work.

See what we’re developing