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6. Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells

Author

Zeng, Jing, primary, Nguyen, My Anh, additional, Liu, Pengpeng, additional, Ferreira da Silva, Lucas, additional, Lin, Linda Y, additional, Justus, David G, additional, Petri, Karl, additional, Clement, Kendell, additional, Porter, Shaina N, additional, Verma, Archana, additional, Neri, Nola R, additional, Rosanwo, Tolulope, additional, Ciuculescu, Marioara-Felicia, additional, Abriss, Daniela, additional, Mintzer, Esther, additional, Maitland, Stacy A, additional, Demirci, Selami, additional, Tisdale, John F, additional, Williams, David A, additional, Zhu, Lihua Julie, additional, Pruett-Miller, Shondra M, additional, Pinello, Luca, additional, Joung, J. Keith, additional, Pattanayak, Vikram, additional, Manis, John P, additional, Armant, Myriam, additional, Pellin, Danilo, additional, Brendel, Christian, additional, Wolfe, Scot A, additional, and Bauer, Daniel E, additional

Published
2023
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7. Therapeutic Gene Editing of HSCs Ex Vivo without in Vitro Culture Avoids Genotoxicity, Simplifies Procedures, and Preserves Efficiency and Stemness

Author

Zeng, Jing, primary, Nguyen, My Anh, additional, Ciuculescu, Marioara-Felicia, additional, Mintzer, Esther, additional, Liu, Pengpeng, additional, Lin, Linda Yingqi, additional, Rosanwo, Tolulope O, additional, Verma, Archana, additional, Neri, Nola, additional, Maitland, Stacy A., additional, Richter, Alden, additional, Justus, David G., additional, Clement, Kendell, additional, Brendel, Christian, additional, Pinello, Luca, additional, Manis, John P, additional, Armant, Myriam, additional, Wolfe, Scot A., additional, and Bauer, Daniel E., additional

Published
2022
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8. Efficient Homology-Directed Repair with Circular Single-Stranded DNA Donors

Author

Iyer, Sukanya, primary, Mir, Aamir, additional, Vega-Badillo, Joel, additional, Roscoe, Benjamin P., additional, Ibraheim, Raed, additional, Zhu, Lihua Julie, additional, Lee, Jooyoung, additional, Liu, Pengpeng, additional, Luk, Kevin, additional, Mintzer, Esther, additional, Guo, Dongsheng, additional, Soares de Brito, Josias, additional, Emerson, Charles P., additional, Zamore, Phillip D., additional, Sontheimer, Erik J., additional, and Wolfe, Scot A., additional

Published
2022
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9. Combined +58 and +55 BCL11A enhancer Editing Yields Exceptional Efficiency, Specificity and HbF Induction in Human and NHP Preclinical Models

Author

Zeng, Jing, primary, Demirci, Selami, additional, Nguyen, My Anh, additional, Lin, Linda Yingqi, additional, Maitland, Stacy A., additional, Mintzer, Esther, additional, Wu, Yuxuan, additional, Pellin, Danilo, additional, Tangprasittipap, Amornrat, additional, Vong, Chokdee, additional, Porter, Shaina N., additional, Luk, Kevin, additional, Liu, Pengpeng, additional, Katta, Varun, additional, Ciuculescu, Marioara-Felicia, additional, Abriss, Daniela, additional, Hsu, Jonathan, additional, Uchida, Naoya, additional, Essawi, Khaled, additional, Donahue, Robert, additional, Petri, Karl, additional, Pattanayak, Vikram, additional, Pinello, Luca, additional, Brendel, Christian, additional, Williams, David A, additional, Manis, John P, additional, Tsai, Shengdar Q., additional, Pruett-Miller, Shondra M., additional, Joung, J. Keith, additional, Songdej, Duantida, additional, Hongeng, Suradej, additional, Armant, Myriam, additional, Wolfe, Scot A., additional, Tisdale, John F., additional, and Bauer, Daniel E., additional

Published
2021
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14. Precision Cas9 Genome Editing in vivo with All-in-one, Self-targeting AAV Vectors

Author

Ibraheim, Raed, primary, Tai, Phillip W. L., additional, Mir, Aamir, additional, Javeed, Nida, additional, Wang, Jiaming, additional, Rodríguez, Tomás, additional, Nelson, Samantha, additional, Khokhar, Eraj, additional, Mintzer, Esther, additional, Maitland, Stacy, additional, Cao, Yueying, additional, Tsagkaraki, Emmanouela, additional, Wolfe, Scot A., additional, Wang, Dan, additional, Pai, Athma A., additional, Xue, Wen, additional, Gao, Guangping, additional, and Sontheimer, Erik J., additional

Published
2020
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15. Efficient Homology-directed Repair with Circular ssDNA Donors

Author

Iyer, Sukanya, primary, Mir, Aamir, additional, Vega-Badillo, Joel, additional, Roscoe, Benjamin P., additional, Ibraheim, Raed, additional, Zhu, Lihua Julie, additional, Lee, Jooyoung, additional, Liu, Pengpeng, additional, Luk, Kevin, additional, Mintzer, Esther, additional, Soares de Brito, Josias, additional, Zamore, Philip D., additional, Sontheimer, Erik J., additional, and Wolfe, Scot A., additional

Published
2019
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16. Enhanced Cas12a editing in mammalian cells and zebrafish

Author

Liu, Pengpeng, primary, Luk, Kevin, additional, Shin, Masahiro, additional, Idrizi, Feston, additional, Kwok, Samantha, additional, Roscoe, Benjamin, additional, Mintzer, Esther, additional, Suresh, Sneha, additional, Morrison, Kyle, additional, Frazão, Josias B, additional, Bolukbasi, Mehmet Fatih, additional, Ponnienselvan, Karthikeyan, additional, Luban, Jeremy, additional, Zhu, Lihua Julie, additional, Lawson, Nathan D, additional, and Wolfe, Scot A, additional

Published
2019
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17. Majorana DUSEL R&D Final Report

Author

Fast, James E., primary, Hoppe, Eric W., additional, Mintzer, Esther E., additional, Aalseth, Craig E., additional, Day, Anthony R., additional, Gerlach, David C., additional, Farmer, Orville T., additional, Liezers, Martin, additional, Lepel, Elwood A., additional, Miley, Harry S., additional, and Edwards, Danny J., additional

Published
2010
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18. Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing

Author

Yin, Hao, primary, Song, Chun-Qing, additional, Suresh, Sneha, additional, Wu, Qiongqiong, additional, Walsh, Stephen, additional, Rhym, Luke Hyunsik, additional, Mintzer, Esther, additional, Bolukbasi, Mehmet Fatih, additional, Zhu, Lihua Julie, additional, Kauffman, Kevin, additional, Mou, Haiwei, additional, Oberholzer, Alicia, additional, Ding, Junmei, additional, Kwan, Suet-Yan, additional, Bogorad, Roman L, additional, Zatsepin, Timofei, additional, Koteliansky, Victor, additional, Wolfe, Scot A, additional, Xue, Wen, additional, Langer, Robert, additional, and Anderson, Daniel G, additional

Published
2017
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20. Combined +58 and +55 BCL11Aenhancer Editing Yields Exceptional Efficiency, Specificity and HbF Induction in Human and NHP Preclinical Models

Author

Zeng, Jing, Demirci, Selami, Nguyen, My Anh, Lin, Linda Yingqi, Maitland, Stacy A., Mintzer, Esther, Wu, Yuxuan, Pellin, Danilo, Tangprasittipap, Amornrat, Vong, Chokdee, Porter, Shaina N., Luk, Kevin, Liu, Pengpeng, Katta, Varun, Ciuculescu, Marioara-Felicia, Abriss, Daniela, Hsu, Jonathan, Uchida, Naoya, Essawi, Khaled, Donahue, Robert, Petri, Karl, Pattanayak, Vikram, Pinello, Luca, Brendel, Christian, Williams, David A, Manis, John P, Tsai, Shengdar Q., Pruett-Miller, Shondra M., Joung, J. Keith, Songdej, Duantida, Hongeng, Suradej, Armant, Myriam, Wolfe, Scot A., Tisdale, John F., and Bauer, Daniel E.

Abstract

Targeting the BCL11Aerythroid enhancer by gene editing is a promising approach to fetal hemoglobin induction for beta-hemoglobinopathies. HbF levels vary widely among individuals, suggesting potential heterogeneity in HbF responses after therapeutic intervention. We hypothesize that maximizing both gene edit frequency and HbF induction potential could promote consistently favorable clinical outcomes. Here we compared CRISPR-Cas9 endonuclease editing of the BCL11A+58 enhancer with alternative gene modification approaches, including +55 erythroid enhancer editing alone or in combination with the +58 enhancer, as well as editing targeting the HBG1/2promoter -115 BCL11A binding site and transduction by an shRNA knocking down the BCL11A transcript in erythroid precursors. We found that combined targeting of the BCL11A+58 and +55 enhancers with 3xNLS-SpCas9 and two sgRNAs resulted in the most potent HbF induction (52.4%±6.3%) of tested approaches (BCL11A+58 editing alone, 29.1%±3.9%; BCL11A+55 editing alone, 34.8±5.1%; HBG1/2promoter editing, 34.1% ±5.4%; shmiR-BCL11A, 32.2%±4.4%; mock, 7.6%±3.4%). Based on assays in bulk and single cell derived erythroid cultures and xenografted immunodeficient mice, we found that disruption of core half E-box/GATA motifs at both the +58 and +55 enhancers was associated with greatest HbF induction, whether by small indels, interstitial 3.1 kb deletion, or 3.1 kb inversion. Rare gene edited clones with alleles that only partially disrupted these motifs were associated with intermediate HbF induction phenotypes. Combined editing of BCL11A+58 and +55 enhancers was compatible with HSC self-renewal in primary and secondary xenotransplant, with intact lymphoid, myeloid and erythroid repopulation. We conducted gene-edited cell product manufacturing process development and developed conditions using a MaxCyte electroporation instrument achieving mean 97.3±1.8% gene edits and 88.9%±6.4% viability 24 hours after electroporation in 3 engineering runs at clinical scale. We obtained similar results at small-scale with plerixafor-mobilized HSPCs from sickle cell disease (SCD) donors or G-CSF mobilized PBMCs from transfusion-dependent beta-thalassemia (TDT) donors, including 94.2%±4.4%, 99.5%±0.3% and 91.8%±6.3% of gene edits in engrafting cells from NBSGW 16 week mouse bone marrow of healthy, SCD and TDT donors respectively. Off-target analyses by pooled amplicon sequencing of 601 candidate off-target sites for the +58 and +55 targeting sgRNAs, nominated by a range of computational (CRISPRme) and experimental (GUIDE-seq and ONE-seq) methods, did not identify reference genome off-target edits at a sensitivity of 0.1% allele frequency. We evaluated +58/+55 enhancer combined targeting in nonhuman primates by performing ribonucleoprotein (RNP) electroporation in rhesus macaque mobilized peripheral blood CD34+ HSPCs with autologous re-infusion following busulfan myeloablation. We observed highly efficient gene edit frequency (85.2%, 88.8% and 84.9%) and durable HbF induction (26.4%, 57.5%, and 45.9% F-cells and 12.7%, 41.9%, and 28% gamma-globin) in the peripheral blood in 3 animals at most recent recorded time point post infusion (127, 78, and 54 weeks respectively). Single colony analyses and bulk ddPCR and unidirectional sequencing demonstrated that the long-term engrafting cells displayed a similar distribution of indels, 3.1 kb deletions, and 3.1 kb inversions as the input cell products. Erythroid stress due to hydroxyurea treatment, with or without phlebotomy, was associated with substantially augmented HbF responses (to 75.9%, 88.2%, and 57.8% F-cells and 47.9%, 68%, and 35.7% gamma-globin). No hematologic or other toxicities attributable to gene editing were observed.

Published
2021
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21. Comparative Transcriptome Analysis of Acne vulgaris, Rosacea, and Hidradenitis Suppurativa Supports High Dose Dietary Zinc as a Therapeutic Agent.

Author

Li L, Hajam I, McGee JS, Tang Z, Zhang Y, Badey N, Mintzer E, Zhang Z, Liu GY, Church GM, and Wang Y

Abstract

Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. We also identified high dose dietary zinc as a potential therapeutic agent and validated its efficacy in an acne mouse model., Competing Interests: CONFLICT OF INTEREST All G.M.C COI are listed here: http://arep.med.harvard.edu/gmc/tech.html. All other authors report no conflict of interest.

Published
2023
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22. Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.

Author

Zeng J, Nguyen MA, Liu P, Ferreira da Silva L, Lin LY, Justus DG, Petri K, Clement K, Porter SN, Verma A, Neri NR, Rosanwo T, Ciuculescu MF, Abriss D, Mintzer E, Maitland SA, Demirci S, Tisdale JF, Williams DA, Zhu LJ, Pruett-Miller SM, Pinello L, Joung JK, Pattanayak V, Manis JP, Armant M, Pellin D, Brendel C, Wolfe SA, and Bauer DE

Abstract

Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for β-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here we compared combined CRISPR-Cas9 endonuclease editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. We found that combined targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two sgRNAs resulted in superior HbF induction, including in engrafting erythroid cells from sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers. We corroborated prior observations that double strand breaks (DSBs) could produce unintended on- target outcomes in hematopoietic stem and progenitor cells (HSPCs) such as long deletions and centromere-distal chromosome fragment loss. We show these unintended outcomes are a byproduct of cellular proliferation stimulated by ex vivo culture. Editing HSPCs without cytokine culture bypassed long deletion and micronuclei formation while preserving efficient on-target editing and engraftment function. These results indicate that nuclease editing of quiescent hematopoietic stem cells (HSCs) limits DSB genotoxicity while maintaining therapeutic potency and encourages efforts for in vivo delivery of nucleases to HSCs.

Published
2023
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