Genetic therapies for sickle cell disease

Area of Science:

• Hematology and Genetic Medicine
• Cell and Gene Therapy

Background:

• Sickle cell disease (SCD) has had limited novel therapeutic options for decades.
• Autologous hematopoietic stem cell (HSC) based genetic therapies are emerging as potential curative treatments.
• Lentiviral gene therapy (GT) and genome editing (GE) show significant promise for SCD.

Purpose of the Study:

• To review current gene therapy (GT) and genome editing (GE) strategies for SCD.
• To highlight critical next steps for optimizing these autologous cell-based genetic therapies.
• To address challenges in HSC collection, conditioning, and patient access.

Main Methods:

• Review of current lentiviral GT strategies, including gene addition and BCL11A regulation for fetal hemoglobin induction.
• Evaluation of genome editing (GE) techniques for sickle hemoglobin mutation repair or fetal hemoglobin elevation.
• Discussion of HSC collection methods, including peripheral mobilization with plerixafor.
• Consideration of conditioning regimens and their associated toxicities.
• Analysis of cost and access issues for widespread adoption of genetic therapies.

Main Results:

• Lentiviral GT has shown promising clinical trial results and is being evaluated in open trials for SCD.
• Genome editing (GE) techniques are advancing and expected to enter clinical trials soon.
• Plerixafor-based mobilization is a promising approach for HSC collection in SCD patients.
• Myeloablative conditioning poses risks, necessitating the development of novel, less toxic regimens.

Conclusions:

• Autologous HSC-based genetic therapies, including GT and GE, are nearing clinical application for SCD.
• Optimization requires addressing HSC collection challenges, developing safer conditioning, and ensuring equitable access.
• Collaborative efforts are essential for the successful implementation and global availability of these advanced therapies.