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      In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles

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          Abstract

          Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg –1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells.

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          Most cited references26

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          A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

          Linda Madisen, Theresa Zwingman, Susan M. Sunkin … (2009)
          The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universal responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in a number of Cre-driver lines, including novel Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.
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            Search-and-replace genome editing without double-strand breaks or donor DNA

            Andrew Anzalone, Peyton B. Randolph, Jessie Davis … (2019)
            Summary Most genetic variants that contribute to disease 1 are challenging to correct efficiently and without excess byproducts 2–5 . Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed >175 edits in human cells including targeted insertions, deletions, and all 12 types of point mutations without requiring double-strand breaks or donor DNA templates. We applied prime editing in human cells to correct efficiently and with few byproducts the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay-Sachs disease (requiring a deletion in HEXA), to install a protective transversion in PRNP, and to precisely insert various tags and epitopes into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, complementary strengths and weaknesses compared to base editing, and much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle can correct up to 89% of known genetic variants associated with human diseases.
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              CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

              Haydar Frangoul, David Altshuler, M Cappellini … (2020)
              Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nano Lett
                Journal ID (iso-abbrev): Nano Lett
                Journal ID (publisher-id): nl
                Journal ID (coden): nalefd
                Title: Nano Letters
                Publisher: American Chemical Society
                ISSN (Print): 1530-6984
                ISSN (Electronic): 1530-6992
                Publication date (Electronic): 29 March 2023
                Publication date Collection: 12 April 2023
                Volume: 23
                Issue: 7
                Pages: 2938-2944
                Affiliations
                [† ]Department of Chemical Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
                [‡ ]David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
                [§ ]FUJIFILM Pharmaceuticals U.S.A., Inc. , Cambridge, Massachusetts 02142, United States
                [∥ ]Harvard-Massachusetts Institute of Technology, Division of Health Science and Technology, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
                [⊥ ]Institute for Medical Engineering and Science, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States
                Author notes
                Author information
                https://orcid.org/0000-0003-0151-4903
                Article
                DOI: 10.1021/acs.nanolett.3c00304
                PMC ID: 10103292
                PubMed ID: 36988645
                SO-VID: 24dd2b0c-3655-42ed-9a42-c62e2b8d2307
                Copyright © © 2023 American Chemical Society
                License:

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 24 January 2023
                Date revision received : 23 March 2023
                Funding
                Funded by: National Heart, Lung, and Blood Institute, doi 10.13039/100000050;
                Award ID: 5R01HL162564
                Funded by: Fujifilm Corporation, doi 10.13039/501100002424;
                Award ID: NA
                Funded by: National Cancer Institute, doi 10.13039/100000054;
                Award ID: P30-CA014051
                Categories
                Subject: Letter
                Custom metadata
                document-id-old-9 nl3c00304
                document-id-new-14 nl3c00304
                ccc-price

                ScienceOpen disciplines: Nanotechnology
                Keywords: lipid nanoparticle,rna,hematopoietic stem cells,antibody targeting,blood disorders
                Data availability:
                ScienceOpen disciplines: Nanotechnology
                Keywords: lipid nanoparticle, rna, hematopoietic stem cells, antibody targeting, blood disorders

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