Utilizing epigenetic regulators to improve HSC-based lentiviral gene therapy

Area of Science:

• Hematology
• Gene Therapy
• Epigenetics

Background:

• Hematopoietic stem cell (HSC) transplantation is curative for various diseases.
• Challenges exist in collecting and expanding HSCs ex vivo for gene therapy, limiting treatment efficacy.
• Optimizing HSC expansion is crucial for successful gene correction strategies.

Purpose of the Study:

• To optimize ex vivo culture conditions for hematopoietic stem cell (HSC) expansion for gene therapy.
• To investigate the role of epigenetic regulators in enhancing HSC expansion and lentiviral (LV) gene therapy effectiveness.
• To improve the efficiency of HSC transduction for gene correction applications.

Main Methods:

• Explored the use of epigenetic regulators, specifically quisinostat (histone deacetylase inhibitor) and CPI203 (bromodomain inhibitor).
• Assessed ex vivo HSC expansion using xenotransplantation assays and single-cell RNA sequencing.
• Evaluated lentiviral (LV) transduction efficiency and HSC numbers in culture protocols with and without epigenetic regulators.

Main Results:

• Quisinostat and CPI203 promoted ex vivo expansion of functional HSCs.
• Epigenetic regulators mitigated the loss of HSCs observed during LV transduction in standard culture protocols.
• Quisinostat addition significantly improved LV transduction efficiency in HSCs and early progenitors.

Conclusions:

• Epigenetic regulators can enhance ex vivo expansion of functional hematopoietic stem cells (HSCs).
• Optimized culture conditions using quisinostat or CPI203 show potential for improving HSC-based gene therapy.
• These findings highlight the clinical applicability of epigenetic regulators in advancing HSC gene correction therapies.