Challenges and limitations of mobilization and stem cell collection for gene therapy of sickle cell disease

Q: Why is stem cell collection a critical step for gene therapy in sickle cell disease?

Gene therapy requires transplantation of gene-modified autologous hematopoietic stem cells. Many manufacturing steps reduce CD34+ cells, so large starting collections are needed to reach the final therapeutic dose.

Q: What role does transfusion medicine play in managing sickle cell disease?

Transfusion medicine supports patients through mobilization and apheresis collection of peripheral blood stem cells, and it supports transplant workflows using standard or exchange transfusion strategies.

Q: Why is there no universal standard for mobilization and stem cell collection protocols?

The document highlights that lack of standardized protocols describing the optimal preparative regimen, mobilization, and collection approach remains a significant barrier to successful outcomes in cellular gene therapy.

Sep 29, 2026

Uploaded by Rainbow Cat

Sickle cell disease is a hereditary hemolytic anemia with major morbidity and shortened lifespan, driven by hemoglobin S polymerization and resulting cellular damage. Allogeneic transplantation can cure but is limited by donor availability and transplant risks such as graft-versus-host disease. Gene therapy using autologous gene-modified hematopoietic stem cells depends on collecting and processing sufficient CD34+ cells, yet optimal mobilization and collection regimens remain incompletely standardized, creating a key barrier to successful cellular gene therapy manufacturing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

Pathophysiology of sickle cell disease

Limitations of current curative options

Rationale for autologous gene therapy

Mobilization and stem cell collection challenges

ADVANCES VIEWPOINT Challenges and limitations of mobilization and stem cell collection for gene therapy of sickle cell disease Yvette C. Tanhehco, 1 Suzanne Thibodeaux,2 Patricia A. Shi,3 Stella T. Chou,4 Shannon A. Kelly,5 Grace Fortes Monis,6 Carly Newton,7 Kamille West-Mitchell,8 Yan Zheng,9 Christine Fernandez, 10 Christina Anderson,10, 11 Kimberly Ching,12 Victoria Coleman-Cowger,14 Adrienne Shapiro,15 and John P Manis 12, 13 1 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY; 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO; 3 Clinical Research in Sickle Cell Disease, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY; 4 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA; 5 Department of Pediatrics, University of California San Francisco Benioff Children’s Hospital Oakland, Oakland, CA; 6 Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA; 7Apheresis Clinical Marketing, Terumo Blood and Cell Technologies, Lakewood, CO; 8 Department of Transfusion Medicine, National Institutes of Health, Bethesda, MA; 9 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN; 10 CRISPR Therapeutics, Boston, MA; 11 bluebird bio, Somerville, MA; 12 Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA; 13 Department of Pathology, Harvard Medical School, Boston, MA; 14The Emmes Company, Rockville, MD; and 15Axis Advocacy, Pasadena, CA Sickle cell disease (SCD) is a hemolytic anemia that afflicts millions of people worldwide and continues to carry high morbidity and reduced life expectancy. Allogeneichematopoietic stem cell transplantation was the only standard-of-care option for cure before the US Food and Drug Administration’s approval of 2 cellular drugs. Transfusion medicine plays a pivotal role in supporting patients through mobilization and apheresis collection of peripheral blood stem cells and through transplant using standard or exchange transfusion strategies. Despite these advances, obtaining sufficient cells to generate a cellular gene therapy product and lack of standardized protocols that describe the optimal preparative regimen, mobilization, and collection of stem cells present a significant barrier to success. Our working group, convened as part of the National Heart, Lung, and Blood Institute–funded Cure Sickle Cell Initiative, sought to identify gaps in our understanding of these processes to improve advanced cell therapies for SCD. Introduction Sickle cell disease (SCD) is an inherited hemolytic anemia that can profoundly affect the health and lifespan of affected patients.1 It is a hemoglobinopathy characterized by a base substitution in the β-globin gene that results in a single amino acid change leading to the production of hemoglobin S (HbS) . HbS polymerizes when deoxygenated, causing the red blood cell (RBC) to assume a rigid sickle shape that contributes to anemia, vaso-occlusion, intravascular hemolysis, endothelial injury, and end-organ damage.2,3 Current therapies for SCD include supportive care for infections, disease-modifying medications to reduce the hemolytic burden or vasculopathy, and RBC transfusion.4 Until recently, allogeneic transplantation was the only potentially curative treatment option. The first successful transplants occurred~40 years ago with matched-sibling donors and resulted in stable engraftment and overall survival of >90% .5 However, <20% of patients with SCD have a matched-sibling donor leading to other donor sources being used with encouraging results.6, 7 Despite the improved outcomes and survival in Submitted 4 February 2025; accepted 25 June 2025; prepublished online on Blood Advances First Edition 4 August 2025. [https://doi.org/10.1182/](https://doi.org/10.1182/)[ ](https://doi.org/10.1182/)[bloodadvances.2025016054]

FAQs

Why is stem cell collection a critical step for gene therapy in sickle cell disease?

Gene therapy requires transplantation of gene-modified autologous hematopoietic stem cells. Many manufacturing steps reduce CD34+ cells, so large starting collections are needed to reach the final therapeutic dose.

What role does transfusion medicine play in managing sickle cell disease?

Transfusion medicine supports patients through mobilization and apheresis collection of peripheral blood stem cells, and it supports transplant workflows using standard or exchange transfusion strategies.

Why is there no universal standard for mobilization and stem cell collection protocols?

The document highlights that lack of standardized protocols describing the optimal preparative regimen, mobilization, and collection approach remains a significant barrier to successful outcomes in cellular gene therapy.

Sep 29, 2026

Uploaded by Rainbow Cat