Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells

Omer-Javed, Attya; Pedrazzani, Gabriele; Albano, Luisa; Ghaus, Sherash; Latroche, Claire; Manzi, Maura; Ferrari, Samuele; Fiumara, Martina; Jacob, Aurélien; Vavassori, Valentina; Nonis, Alessandro; Canarutto, Daniele; Naldini, Luigi

doi:10.1016/j.cell.2022.04.039

Cited by 30 publications

(19 citation statements)

References 85 publications

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“… 88 , 89 Recently, non-toxic conditioning drugs such as humanized antibodies against HSPC receptors or mobilization-based chemotherapy-free engraftment have been developed to vacate niches and create space and engraftment in bone marrow, and are being intensively investigated in non-clinical and clinical trials ( ClinicalTrial.Gov ID: NCT04429191). 90 , 91 , 92 Furthermore, in vivo HSC transduction infusing vector directly in the bone marrow niche are rapidly progressing 93 as well as the use of G-CSF1R inhibitor drugs to make space for genetically modified HSC-derived microglia in the brain. 94 , 95 …”

Section: Discussionmentioning

confidence: 99%

Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease

Dogan

Barese

Schindler

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Section: Discussionmentioning

confidence: 99%

Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease

Dogan

Barese

Schindler

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…Recently, reconstitution of gene-corrected autologous HSCTs was seen in the absence of conditioning in patients with Fanconi syndrome, a disease of inherited bone marrow failure, due to a growth advantage of the gene-corrected reconstituted hematopoietic cells compared with the uncorrected cells ( 34 ). Preclinical work has also demonstrated that mobilization with G-CSF and plerixafor provides a niche for autologous HSPCs to engraft ( 35 ). Our previous work has shown an engraftment advantage of augmented HSPCs ( 13 ), and most of our patients were mobilized before the cell infusion with G-CSF and plerixafor, setting a stage for possible engraftment and long-term survival advantage of the augmented cells.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes

et al. 2022

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Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34 + hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.

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“…Others have deployed mRNA to improve engraftment of human hematopoietic stem cells by transient overexpression of CXCR40 (ref. 220 ). The versatility of mRNA is likely to trigger unexplored therapeutic and investigative opportunities in the future.…”

Section: The Scope Of Mrna Therapeuticsmentioning

confidence: 99%

Unlocking the promise of mRNA therapeutics

et al. 2022

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z and enhanced catalysis to the ribosomal complex [32][33][34][35][36] . Optimization of the poly(A) tail length (100-300 nucleotides) has proven critical in balancing the synthetic capability of a given mRNA 34,36 . Similarly, improved 5′ cap analogs not only increase translational capacity but also enhance capping efficiency, from 70% to 95%, greatly improving the in vitro transcription process 32,37 . The composition of the 3′ and 5′ UTRs can also be customized for the target cell of interest, increasing the efficiency and tissue specificity of translation 35,38,39 .At present, most mRNA products contain a synthetic UTR sequence from α-globin or β-globin [38][39][40] , but UTR optimization can further improve protein expression by a few fold 41,42 . Careful screening and customization to the target of interest could conceivably offer a wide range of improvements in future UTR sequences, allowing each mRNA to be tailored to the targeted cell and disease-induced microenvironment to maximize protein synthesis per mRNA transcript [41][42][43][44] .Perhaps the most critical advances in mRNA vaccines and therapeutics lie in the discovery that the inclusion of chemically modified nucleosides, particularly in uridine moieties, can markedly increase protein expression after in vitro or in vivo transfection. The chemical modifications of most new RNA formulations to date have been central in intellectual property claims 45,46 . Thus far, over 130 different naturally occurring chemical modifications of RNA have been reported 47,48 . The interest in methylpseudouridine and other modified nucleosides centers on their capacity to greatly reduce (up to 100-fold) detection by the Toll-like receptors of the innate immune system, resulting in an increase in protein expression in vivo compared to unmodified mRNA 40,[49][50][51][52][53] . Combinations of different types of chemical modifications, carriers, for the treatment of chronic conditions. The fifth section provides a comprehensive table and summary of current clinical trends in mRNA therapeutics. Finally, the sixth section considers the scope of mRNA therapeutics and guiding principles for near-term and longer-term clinical development of this novel therapeutic modality.

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Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells

Cited by 30 publications

References 85 publications

Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease

Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease

Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes

Unlocking the promise of mRNA therapeutics

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