Gene editing of hematopoietic stem cells: applications and advances

Unlocking the Curative Potential of Gene Transfer and Editing for Hematopoietic Disorders.

Hematopoietic stem and progenitor cells (HSPCs) gene therapy may transform the therapeutic landscape for inherited hematological disorders and already offers potentially curative options for some diseases, including inborn errors of immunity and β-hemoglobinopathies. Its continued success relies on further refinement of gene transfer technologies, gene editing tools such as CRISPR-Cas, and optimized ex vivo HSPC manipulation protocols that ensure robust, long-term engraftment and clonal diversity with reduced-toxicity, non-genotoxic conditioning strategies. Here, we review recent developments and refinements in gene transfer and editing technologies for HSPCs, while also discussing the critical limitations and hurdles to clinical translation, as recently presented at the New Investigator Committee Gene Therapy webinar. Future directions must prioritize integrating technological innovation with the development of equitable and simplified models to reduce costs and ensure that these life-saving cellular therapies reach patients worldwide. Teaser abstract Hematopoietic stem and progenitor cells (HSPCs) gene therapy is advancing rapidly, with lentiviral gene transfer, genome editing, and emerging in vivo delivery approaches expanding the therapeutic landscape for inherited hematologic disorders. Recent clinical successes have demonstrated the potential for durable correction, while ongoing refinements continue to improve safety, efficacy, and feasibility. Key challenges remain in genotoxicity, conditioning toxicity, manufacturing scalability, and equitable global access.

Gene therapy approaches for inborn errors of immunity: from bench to bedside.

INTRODUCTION Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic hematopoietic stem cell transplantation for IEIs. AREAS COVERED Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition - which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis - to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene editing technologies, including CRISPR/Cas9, and base/prime editing, which offer targeted correction with minimized genotoxicity. EXPERT OPINION Recent milestones in diseases like Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.

Base Editing Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of X-Linked Severe Combined Immunodeficiency

It is concluded from preliminary data that gene therapy using BE HSPCs appear very promising for achieving an earlier and more robust multi-lineage immune reconstitution in adult patients using BE HSPCs.

[Hematopoietic cell transplantation in the era of genome analysis].

Translating CRISPR to Practice in the Clinic: Transformative Therapy in Hemoglobinopathies and Emerging Applications in Malignancies.

Hemoglobinopathies provide the first clinically validated delivery model for CRISPR therapeutics, and offers a donor-independent alternative to allogeneic hematopoietic stem-cell transplantation without graft rejection or graft-versus-host disease.

Modeling myeloid cell development in health and disease using induced pluripotent stem cells

Key applications of iPSC technology in hemato-oncology are summarized, its major advantages and current limitations are discussed, and emerging directions are highlighted, including scalable iPSC-derived blood cell therapies for inherited and acquired bone marrow failure syndromes and leukemia.