Non-Genotoxic Conditioning Approach for Autologous Hematopoietic Stem Cell Therapies through Transient mRNA Engineering Using Vector-Free Microfluidic Cell Squeeze® Technology

Silva, Murillo; Bartlett, Cara; Hanson, Jacquelyn L.; Gilbert, Jonathan B.; Bridgen, Devin

doi:10.1182/blood-2022-169892

Cited by 1 publication

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“…Preliminary data showed that one dose of the ADC resulted in a fully myeloablative effect with greater than 99% HSPC depletion, and was well-tolerated with no adverse effects, unlike NHPs treated with high dose busulfan. An additional nongenotoxic conditioning approach to aid engraftment of ex vivo transduced HSPCs involves the transient modification of HSPC utilizing mRNA constructs encoding homing receptors, like CXCR4, or survival factors such as BCL2 [ 100 ].…”

Section: Bone Marrow Conditioning To Facilitate Engraftment Of Gene-m...mentioning

confidence: 99%

Gene Therapy for β-Hemoglobinopathies: From Discovery to Clinical Trials

Segura

Ayoub

Hart

et al. 2023

Viruses

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Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the 20th and 21st centuries. Extensive characterization of the globin gene locus, accompanied by pioneering work on the utilization of viruses as human gene delivery tools in human hematopoietic stem and progenitor cells (HPSCs), has led to transformative and successful therapies via autologous hematopoietic stem-cell transplant with gene therapy (HSCT-GT). Due to the advanced understanding of the β-globin gene cluster, the first diseases considered for autologous HSCT-GT were two prevalent β-hemoglobinopathies: sickle cell disease and β-thalassemia, both affecting functional β-globin chains and leading to substantial morbidity. Both conditions are suitable for allogeneic HSCT; however, this therapy comes with serious risks and is most effective using an HLA-matched family donor (which is not available for most patients) to obtain optimal therapeutic and safe benefits. Transplants from unrelated or haplo-identical donors carry higher risks, although they are progressively improving. Conversely, HSCT-GT utilizes the patient’s own HSPCs, broadening access to more patients. Several gene therapy clinical trials have been reported to have achieved significant disease improvement, and more are underway. Based on the safety and the therapeutic success of autologous HSCT-GT, the U.S. Food and Drug Administration (FDA) in 2022 approved an HSCT-GT for β-thalassemia (Zynteglo™). This review illuminates the β-globin gene research journey, adversities faced, and achievements reached; it highlights important molecular and genetic findings of the β-globin locus, describes the predominant globin vectors, and concludes by describing promising results from clinical trials for both sickle cell disease and β-thalassemia.

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Section: Bone Marrow Conditioning To Facilitate Engraftment Of Gene-m...mentioning

confidence: 99%