Aaron Edwards

Aaron Edwards

Cambridge, Massachusetts, United States
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About

As the Co-Founder and CEO of KiraGen Bio, I'm proud to lead a team of innovators…

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Experience

  • KiraGen Bio Graphic

    KiraGen Bio

    Boston, Massachusetts, United States

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    Danville, Kentucky, United States

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    Cambridge, Massachusetts, United States

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    Boston, Massachusetts, United States

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    Cambridge, Massachusetts, United States

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    Boston, Massachusetts, United States

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    Boston, Massachusetts, United States

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    San Rafael, California, United States

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    Boston, Massachusetts, United States

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    Cambridge, Massachusetts, United States

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    Cambridge, Massachussetts

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    Cambridge, Massachusetts

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    Cambridge, Massachusetts

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    Cambridge, Massachusetts

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    Cambridge, Massachusetts

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    Department of Chemistry

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    Department of Molecular Oncology

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    Department of Molecular Oncology

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    Department of Biology

Education

Publications

  • Cytosine Base Editing Enables Quadruple-Edited Allogeneic CAR-T Cells for T-ALL

    Blood

    Allogeneic chimeric antigen receptor T cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CART have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells with between 90-99% efficiency to silence gene expression without creating DSBs, greatly reducing…

    Allogeneic chimeric antigen receptor T cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CART have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells with between 90-99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared to CRISPR-Cas9. Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using four simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells with high potential for clinical translation for relapsed and refractory T-ALL.

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  • Highly efficient multiplexed base editing enables the development of universal CD7-targeting CAR-T cells to treat T-ALL

    Society for Immunotherapy of Cancer

    Presentation at SITC

  • Directed evolution of adenine base editors with increased activity and therapeutic application

    Nature Biotechnology

    The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5–A7 and ~3.2× higher editing at positions A3–A4 and A8–A10 compared with ABE7.10. Non-NGG PAM variants…

    The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5–A7 and ~3.2× higher editing at positions A3–A4 and A8–A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2 with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98–99% target modification, which is maintained when multiplexed across three loci. Delivered as messenger RNA, ABE8s induce no significant levels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.

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  • Base editors generate allogeneic CAR-T cells with no detectable genomic rearrangements and reduced genotoxicity

    ASGCT

    Oral presentation at ASGCT

    See publication

  • In vivo gene editing of the murine Pcsk9 locus using lipid nanoparticle delivered megaTAL mRNA (Poster)

    American Society of Gene and Cell Therapy

  • Gene Editing of TRAC Locus Utilizing megaTAL Nucleases Increases Expression of Transgenic TCRs Delivered via Lentiviral Vector-Mediated Gene Transfer (Poster)

    American Society of Hematology

  • Unbiased off-target ID for megaTAL nucleases (Poster)

    Advances in Genome Biology and Technology

  • Design of multi-cistronic, self-replicating RNA replicons with enhanced expression profiles (Poster)

    Novartis Vaccines Science Day

  • Sequential Targeted Delivery of Paclitaxel and Camptothecin Using a Cross-Linked “Nanosponge” Network for Lung Cancer Chemotherapy

    Molecular Pharmaceutics

    The applicability of a HVGGSSV peptide targeted “nanosponge” drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer model. Schedule-dependent combination treatment with nanoparticle paclitaxel (NP PTX) and camptothecin (NP CPT) was studied in vitro using flow cytometry and confocal imaging to analyze changes in cell cycle, microtubule morphology, apoptosis, and cell proliferation…

    The applicability of a HVGGSSV peptide targeted “nanosponge” drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer model. Schedule-dependent combination treatment with nanoparticle paclitaxel (NP PTX) and camptothecin (NP CPT) was studied in vitro using flow cytometry and confocal imaging to analyze changes in cell cycle, microtubule morphology, apoptosis, and cell proliferation. Results showed significant G2/M phase cell cycle arrest, changes in microtubule dynamics that produced increased apoptotic cell death and decreased proliferation with initial exposure to NP PTX, followed by NP CPT in lung cancer cells. In vivo molecular imaging and TEM studies validated HVGGSSV-NP tumor binding at 24 h and confirmed the presence of Nanogold labeled HVGGSSV-NPs in tumor microvascular endothelial cells. Therapeutic efficacy studies conducted with sequential HVGGSSV targeted NP PTX and NP CPT showed 2-fold greater tumor growth delay in combination versus monotherapy treated groups, and 4-fold greater delay compared to untargeted and systemic drug controls. Analytical HPLC/MS methods were used to quantify drug content in tumor tissues at various time points, with significant paclitaxel and camptothecin levels in tumors 2 days postinjection and continued presence of both drugs up to 23 days postinjection. The efficacy of the NP delivery system in sequential treatments was corroborated in both in vitro and in vivo lung cancer models showing increased G2/M phase arrest and microtubule disruption, resulting in enhanced apoptotic cell death, decreased cell proliferation and vascular density.

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Patents

Courses

  • Biomedical Information

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  • Biostatistics

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  • Cave Ecology

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  • Comprehensive Immunology

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  • Ecology

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  • Evolutionary Genetics

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  • Fundamentals of Biotechnology

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  • Immunology

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  • Introduction to Biochemistry and Molecular Biology

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  • Invertebrate Biology

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  • Medical Biochemistry

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  • Medical Physiology

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  • Microbiology

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  • Organic Chemistry I

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  • Organic Chemistry II

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  • Pharmacology

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  • The Biology of Viruses

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Languages

  • English

    Native or bilingual proficiency

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