GPH101 (Graphite Bio Inc.) is an investigational gene-editing autologous hematopoietic stem cell (HSC) therapy designed to directly correct the genetic mutation that causes sickle cell disease (SCD). Preclinical data presented at Sickle Cell Disease Association of America 49th Annual National Convention 2021 highlights the potential of GPH101 to correct the underlying disease-causing mutation to decrease production of sickle hemoglobin and restore the expression of normal adult hemoglobin with minimal off-targeting, thereby supporting the initiation of Graphite Bio’s Phase 1/2 CEDAR clinical trial to evaluate GPH101 in SCD. The company plans to enroll the first patient before the end of the year. Briefly, GPH101 has the potential to achieve over 60% of gene-corrected beta-globin alleles in vitro with a reduced off-target cleavage by 30-fold, and achieve long-term engraftment (16 weeks) of gene-corrected cells in vivo (NSG mice) with no evidence of genotoxicity, abnormal hematopoiesis, or tumorigenicity, including no detectable chromosomal translocations. In addition, the data showed that gene-corrected red blood cells went from producing 100% sickle hemoglobin to expressing more than 90% normal adult hemoglobin. A copy of the poster presentation is available here. For more information: Graphite Bio’s press release

We are excited to announce the first article by the ClinGen Hemoglobinopathy Variant Curation Expert Panel (https://www.clinicalgenome.org/affiliation/50052/), published in Human Mutation (DOI:10.1002/humu.24280), that discusses the process, challenges and considerations of specifying the ACMG/AMP guidelines for variants related to hemoglobinopathies. The ACMG/AMP guidelines comprise a series of generic criteria for the standardized interpretation and reporting of sequence variants across laboratories. Owing to the varying degrees of subjectivity and uncertainty allowed by these guidelines, the Clinical Genome Resource (ClinGen) assembles Variant Curation Expert Panels (VCEPs) to develop specifications for the ACMG/AMP framework. The ClinGen Hemoglobinopathy VCEP was created collaboratively between the ITHANET Portal (https://www.ithanet.eu/) and the Global Globin Network of the Human Variome Project (http://www.humanvariomeproject.org/gg2020/) for specifying the ACMG/AMP variant curation framework to evaluate all available evidence relevant to hemoglobinopathies and the globin genes, with the aim to standardize the curation and interpretation of variants in different conditions. The Hemoglobinopathy VCEP specifications were approved by ClinGen in April 2021 (Step 2 approval), which initiated the process of further validation and adaptation with known globin gene variants in a pilot study (toward Step 3 approval). The observations by the Hemoglobinopathy VCEP outlined in this article can help highlight the challenges generally encountered during variant curation and interpretation and during the specification of ACMG/AMP guidelines for future VCEPs.

The U.S. Food and Drug Administration (FDA)  has accepted Global Blood Therapeutics’ (GBT’s) supplemental New Drug Application (sNDA) seeking accelerated approval for Oxbryta® (voxelotor) for the treatment of sickle cell disease (SCD) in children ages 4 to 11 years and its New Drug Application (NDA) seeking approval for a new age-appropriate dispersible tablet dosage form of Oxbryta suitable for pediatric patients (i.e., 300 mg grape flavoring tablets). Oxbryta is currently approved by the FDA in a tablet dosage form to treat SCD in patients age 12 years and older. Oxbryta is a first-in-class therapy that directly targets hemoglobin polymerization, the root cause of red blood cell sickling in SCD. For more information, read GBT press release here. 

Bluebird bio announced it has completed the rolling submission of its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for approval of betibeglogene autotemcel (beti-cel) gene therapy in adult, adolescent and pediatric patients with β-thalassaemia who require regular red blood cell transfusions, across all β genotypes. Beti-cel is already cleared for market in Europe, where it's sold under the brand name Zynteglo. The BLA submission for beti-cel is based on data from Phase 1/2 and Phase 3 Northstar studies, which represent more than 220 patient-years of experience with beti-cel. The FDA previously granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of transfusion-dependent β-thalassemia. If approved, beti-cel will be the first hematopoietic (blood) stem cell (HSC) ex-vivo gene therapy for patients in the United States. Source: bluebirdbio press release