Clinical Update: Graphite Bio Doses First Patient With Potential CRISPR Cure for Sickle Cell Disease

Graphite Bio reports dosing the first patient with its lead CRISPR therapy candidate nula-cel in Phase 1/2 trial for sickle cell disease.

By: Karen O'Hanlon Cohrt - Aug. 31, 2022

Graphite Bio reported earlier this month that the first patient had been dosed with the company's lead CRISPR therapy candidate nulabeglogene autogedtemcel (nula-cel, formerly known as GPH101), in the Phase 1/2 CEDAR trial for sickle cell disease (SCD).

First clinical-stage therapeutic candidate to correct underlying SCD mutation

Nula-cel is the first CRISPR-based therapy candidate designed to correct the causative mutation in SCD (see Fact Box), and as such it is anticipated to provide a permanent cure by targeting the root cause of disease.

The therapeutic strategy behind nula-cel is that CRISPR-based correction of the beta-globin (HBB) gene will decrease sickle haemoglobin (HbS) production and restore adult haemoglobin (HbA) expression, thereby potentially curing SCD by restoring completely normally-functioning red blood cells.

Nula-cel is engineered using patient-derived haematopoietic stem cells (HSCs) that are edited with Cas9-sgRNA gene-editing machinery and a DNA repair template, in a mechanism that essentially cuts the mutation out of the genome and replaces it with the correct sequence.

Cas9-sgRNA is delivered through ribonucleoprotein protein (RNP) complexes while corrected DNA template delivery is achieved through an adeno-associated virus 6 (AAV6) vector.

FACT BOX: Sickle Cell Disease (SCD) and Foetal Haemoglobin

SCD affects approximately 100,000 people in the U.S. alone and many millions of people around the worldwide, making it the most frequently-occuring monogenic disease globally. SCD results from a single-point mutation in the haemoglobin subunit beta (HBB) gene and is associated with a range of symptoms and life-life complications. Vaso-occlusive crises (VOEs or VOCs) are the most commonly encountered complication in severe SCD, and these occur when small blood vessels get blocked because of sickled red blood cells which tend to be stiffer than healthy cells, and because the defective form of haemoglobin seen in SCD (haemoglobin S) renders the red blood cell membranes sticky.

Daily treatment for SCD patients is limited to symptom control, dietary intervention and pain management. While a bone marrow transplant from a healthy matched donor has traditionally been the only (albeit slight) hope of a cure for the haemoglobinopathies, gene-editing technology unleashes the possibility to cure a patient using their own cells. Central to many of the current approaches is foetal haemoglobin (HbF).

HbF is highly expressed and critical during foetal development, but then rapidly suppressed early in life. Extensive research on the molecular mechanisms of the haemoglobinopathies revealed that the B-cell lymphoma/leukaemia 11A gene, BCL11A, is a negative regulator of HbF expression, and that its disruption could restore HbF expression and reverse SCD in mice by compensating for the lack of functional adult haemoglobin. Since the discovery of this so-called haemoglobin switch, reactivation of HbF expression has emerged as a dominating therapeutic strategy for SCD.

The CEDAR trial

The CEDAR trial is a multi-center, open-label study designed to evaluate the safety, efficacy and pharmacodynamics of the new therapeutic candidate in approximatly 15 adult and adolescents with severe SCD. The trial is now enrolling participants at up to five clinical trial sites in the United States. In May of this year, Graphite Bio announced that the FDA had granted Fast Track Designation to (then) GPH101 for the treatment of sickle cell disease (SCD).

The first patient was enroled in the CEDAR trial in November 2021, and at that time dosing was expected to be initiated in the first half of 2022. In March of this year, Graphite Bio announced in a business and financial report that as a result of pressures related to the COVID-19 Omicron variant surge at that time, dosing of the first SCD patient with nula-cel was postponed until the second half of 2022, and that initial proof-of-concept data is expected in 2023.

Pre-clinical data supports curative potential of GPH101

In November 2021, the company presented pre-clinical data for GPH101 at the 49th Annual Sickle Cell Disease Association of America National Convention. This data supported the ability of Graphite Bio's gene-editing platform to precisely and efficiently correct the disease-causing mutation in HBB and restore adult haemoglobin expression with curative potential. The data also revealed minimal off-target effects using Graphite Bio's exclusively licensed high fidelity Cas9 and robust long-term engraftment. Graphite Bio also presented a poster outlining the CEDAR trial, including the mechanism of action of nula-cel, at the 63rd American Society of Hematology (ASH) Annual Meeting in December 2021.

We strive to keep you updated with clinical and pre-clinical news from the CRISPR Medicine field. For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.

Related CMN articles

Disease Roundup: Genomic Medicine Candidates for Sickle Cell Disease. This piece presents the 7 clinical-stage gene-editing approaches to SCD, including CRISPR-Cas9, CRISPR-Cas12a, and base editing.

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