Aug 2026· Experimental Hematology· pp.
105493
· 0 citations· 116 references
Medicine
TL;DR
Recent developments and refinements in gene transfer and editing technologies for HSPCs are reviewed, while also discussing the critical limitations and hurdles to clinical translation, as recently presented at the New Investigator Committee Gene Therapy webinar.
Abstract
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.
Autologous HSC transplantation does not have the previously mentioned problems associated with allogeneic transplantation, and gene editing involving ex vivo genetic modification of HSCs and subsequent reinfusion in a single patient has emerged.
Qiu Li, Hong-Xia Wang, Yu-Qin He et al.· International journal of hem...· 0 citations
The 30-year evolution of autologous gene therapy as a vital alternative to allogeneic hematopoietic stem cell transplantation for IEIs is explored, tracing the transition from early gamma-retroviral gene addition - which successfully restored immunity in severe combined immunodeficiency but carried high risks of insertional mutagenesis and leukemogenesis - to the adoption of safer self-inactivating lentiviral vectors.
Jasmeen Dara, Claire Booth· Expert Opinion on Biological...· 0 citations
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.
Ivan Tesakov, M. Nasri, M. Klimiankou et al.· Frontiers in Immunology· 0 citations
Targeted immunotherapies have transformed the treatment of hematologic malignancies, yet their clinical utility is often constrained by on-target, off-tumor toxicity arising from shared antigen expression between malignant cells and essential healthy tissues. An early approach to mitigate this limitation involved the knockout (KO) of the target antigen in donor hematopoietic stem and progenitor cells (HSPCs). However, this strategy is restricted to markers that are dispensable for normal hematopoietic function. Epitope engineering has emerged as an alternative paradigm to decouple therapeutic susceptibility from physiological function by modifying the target antigen on healthy cells while preserving biological activity. In this review, we discuss recent advances in base and prime editing approaches used for epitope editing. We examine recent preclinical and emerging translational studies of this strategy in both malignant and non-malignant contexts. Finally, we discuss challenges related to editing efficiency, off-target effects, delivery strategies, and long-term safety in hematopoietic stem cells. Collectively, epitope engineering of hematopoietic stem cells represents a versatile platform to expand the therapeutic window of precision immunotherapies and may enable safer, more effective combinatorial treatment strategies for both non-malignant and malignant hematologic conditions.
Joanne Baek, G. Casirati, Pietro Genovese et al.· Blood Advances· 0 citations
Pediatric gene therapy holds transformative potential to provide curative solutions for children, and the establishment of standardized regulatory frameworks, accompanied by robust and transparent AI integration, will be essential to ensure safe, equitable, and scalable translation.
Yinping Pan, Jian Ding, Wenhai Wang et al.· Pediatric Research· 0 citations
Current cell and gene therapies lack clinically practical mechanisms to selectively promote or suppress therapeutic cells in vivo, a limitation that is particularly acute in patients requiring ongoing immunosuppression. This includes gene therapy for immune dysregulation syndromes, and antigen-specific or chimeric antigen receptor (CAR) T-cell therapy for patients requiring immunosuppression (e.g., transplant recipients), where both pathogenic and therapeutic cells may be suppressed. Here, we develop a multiplex prime-editing platform that converts commonly used immunosuppressive drugs into tools for in vivo control of T-cell therapies via defined, pathway-specific drug resistance. Focusing initially on gene therapy, prime editing efficiently edited loci of multiple pathogenic variants associated with immune dysregulation in primary human T-cells and corrected the HAVCR2 driver mutation in T-cells from multiple patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Comprehensive genomic, transcriptional, immunophenotypic, and clonal analyses demonstrated minimal off-target perturbation. Multiplexed gene correction and drug-resistance editing of T-cells from patients with SPTCL enabled selective in vivo expansion of corrected cells under immunosuppressive pressure in humanized mouse models and exhibited retained sensitivity to alternative agents permitting rapid in vivo suppression. Extending this approach, prime edited, drug-resistant antigen-specific and CAR T-cells retained effector function despite pharmacologic immunosuppression, demonstrating the generalizability of this platform to diverse cellular therapies. Together, these findings establish multiplex prime editing as a promising preclinical framework for generating drug-controllable T-cell therapies, enabling selective in vivo modulation in settings where immunosuppression cannot be withdrawn.
E. Bandala-Sanchez, Emma V. Petley, K. Ramsay et al.· Blood· 0 citations
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