Clinical Trial Update: CRISPR Therapy Designed to Cure Sickle Cell Disease

Graphite Bio reported early last year that the FDA had cleared an IND application in December 2020 for the company's lead CRISPR therapy candidate GPH101 for sickle cell disease (SCD).

GPH101 will be assessed in the Phase 1/2 CEDAR trial, a multi-center, open-label study to evaluate the safety, efficacy and pharmacodynamics of the new therapeutic candidate in adult and adolescents with severe SCD. The trial will enrol approximately 15 adult and adolescent participants at up to five clinical trial sites in the United States.

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. Last week, Graphite Bio announced in a business and financial report that as a result of the recent COVID-19 Omicron variant surge on patients, site resources, and operations, the company now plans to dose the first SCD patient with GPH101 in the second half of 2022, with initial proof-of-concept data anticipated in 2023.

In the same press release, Graphite Bio announced that patient enrolment is now ongoing at multiple clinical sites, and that it expects to obtain initial proof-of-concept clinical data for GPH101 in SCD in 2023.

First experimental therapy to correct underlying SCD mutation

GPH101 is the first CRISPR-based therapy candidate designed to correct the HBB point mutation (see Fact Box), and it is anticipated to provide a permanent cure by targeting the root cause of disease.

Correction of the HBB gene leads to a decrease in sickle haemoglobin (HbS) production and restores normal adult haemoglobin (HbA) expression, thereby restoring completely normally-functioning red blood cells.

The candidate 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.

Pre-clinical data supports curative potential of GPH101

In November 2021, the company presented pre-clinical data for GPH101 at the 49^th 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 GPH101, at the 63^rd 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.