Graphite Bio, a clinical-stage, next-generation gene editing company harnessing the power of high-efficiency precision gene repair to develop therapies with the potential to treat or cure serious diseases, today presented preclinical results supporting the use of a single-cell RNA sequencing method to assess gene correction outcomes in patients treated with nulabeglogene autogedtemcel (nula-cel), an investigational gene-edited therapy for sickle cell disease (SCD). The findings are being presented in a poster session at the 64th American Society of Hematology (ASH) Annual Meeting & Exposition taking place virtually and at the Ernest N. Morial Convention Center in New Orleans.
“Our goal is to cure sickle cell disease by directly correcting the underlying disease-causing genetic mutation in order to simultaneously reduce sickle hemoglobin production and restore healthy adult hemoglobin expression, thereby potentially alleviating all complications associated with the disease,” said Josh Lehrer, M.D., M. Phil., chief executive officer of Graphite Bio. “The novel single-cell RNA sequencing method that we developed will help us determine initial gene editing outcomes in patients treated with nula-cel, providing important preliminary information about the potential efficacy of the investigational therapy.”
Graphite Bio’s gene correction approach for SCD involves editing hematopoietic stem cells found in the bone marrow that develop into various types of blood cells such as red blood cells. Since red blood cells lose their nucleus and genomic DNA during maturation, tracking gene editing outcomes in mature red blood cells via nucleic acid sequencing is not possible. However, immature red blood cells called reticulocytes retain RNA that can be sequenced in order to assess gene correction levels.
Based on this knowledge, Graphite Bio scientists sought to develop a single-cell RNA sequencing method that could measure gene editing outcomes in reticulocytes. To establish proof-of-concept and evaluate the accuracy of the method, researchers measured the genetic makeup of reticulocytes from healthy donors (AA), people with sickle cell trait (AS) and those with sickle cell disease (SS), first in a mixture of AA:SS reticulocytes and then in a more complex mixture of AA:AS:SS reticulocytes. Results from both experiments demonstrated the single-cell RNA sequencing method’s ability to precisely and reproducibly measure and differentiate the AA, AS and SS reticulocytes. These data support the use of this method to determine initial gene editing outcomes in patients treated with nula-cel in order to support the clinical development of this investigational therapy.
Source – BusinessWire