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Your search keyword '"Slipek, Nicholas J."' showing total 15 results
Start Over Author "Slipek, Nicholas J." Publication Type Academic Journals
15 results on '"Slipek, Nicholas J."'

3. Evolution of the clinical-stage hyperactive TcBuster transposase as a platform for robust non-viral production of adoptive cellular therapies

Author

Skeate, Joseph G., Pomeroy, Emily J., Slipek, Nicholas J., Jones, Bryan J., Wick, Bryce J., Chang, Jae-Woong, Lahr, Walker S., Stelljes, Erin M., Patrinostro, Xiaobai, Barnes, Blake, Zarecki, Trevor, Krueger, Joshua B., Bridge, Jacob E., Robbins, Gabrielle M., McCormick, Madeline D., Leerar, John R., Wenzel, Kari T., Hornberger, Kathlyn M., Walker, Kirsti, Smedley, Dalton, Largaespada, David A., Otto, Neil, Webber, Beau R., and Moriarity, Branden S.

Published
2024
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4. Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

Author

Palmer, Douglas C., Webber, Beau R., Patel, Yogin, Johnson, Matthew J., Kariya, Christine M., Lahr, Walker S., Parkhurst, Maria R., Gartner, Jared J., Prickett, Todd D., Lowery, Frank J., Kishton, Rigel J., Gurusamy, Devikala, Franco, Zulmarie, Vodnala, Suman K., Diers, Miechaleen D., Wolf, Natalie K., Slipek, Nicholas J., McKenna, David H., Sumstad, Darin, Viney, Lydia, Henley, Tom, Bürckstümmer, Tilmann, Baker, Oliver, Hu, Ying, Yan, Chunhua, Meerzaman, Daoud, Padhan, Kartik, Lo, Winnie, Malekzadeh, Parisa, Jia, Li, Deniger, Drew C., Patel, Shashank J., Robbins, Paul F., McIvor, R. Scott, Choudhry, Modassir, Rosenberg, Steven A., Moriarity, Branden S., and Restifo, Nicholas P.

Published
2022
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5. PLX3397 treatment inhibits constitutive CSF1R-induced oncogenic ERK signaling, reduces tumor growth, and metastatic burden in osteosarcoma

Author

Smeester, Branden A., Slipek, Nicholas J., Pomeroy, Emily J., Laoharawee, Kanut, Osum, Sara H., Larsson, Alex T., Williams, Kyle B., Stratton, Natalie, Yamamoto, Kenta, Peterson, Joseph J., Rathe, Susan K., Mills, Lauren J., Hudson, Wendy A., Crosby, Margaret R., Wang, Minjing, Rahrmann, Eric P., Moriarity, Branden S., and Largaespada, David A.

Published
2020
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6. CRISPR-Cas9 cytidine and adenosine base editing of splice-sites mediates highly-efficient disruption of proteins in primary and immortalized cells

Author

Kluesner, Mitchell G., Lahr, Walker S., Lonetree, Cara-lin, Smeester, Branden A., Qiu, Xiaohong, Slipek, Nicholas J., Claudio Vázquez, Patricia N., Pitzen, Samuel P., Pomeroy, Emily J., Vignes, Madison J., Lee, Samantha C., Bingea, Samuel P., Andrew, Aneesha A., Webber, Beau R., and Moriarity, Branden S.

Published
2021
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10. A Pan-RNase Inhibitor Enabling CRISPR-mRNA Platforms for Engineering of Primary Human Monocytes.

Author

Laoharawee, Kanut, Johnson, Matthew J., Lahr, Walker S., Sipe, Christopher J., Kleinboehl, Evan, Peterson, Joseph J., Lonetree, Cara-lin, Bell, Jason B., Slipek, Nicholas J., Crane, Andrew T., Webber, Beau R., and Moriarity, Branden S.

Subjects
MONOCYTES, ERGONOMICS, TRANSGENE expression, CHEMOKINE receptors, GENE expression, GENE knockout, CANCER cells
Abstract

Monocytes and their downstream effectors are critical components of the innate immune system. Monocytes are equipped with chemokine receptors, allowing them to migrate to various tissues, where they can differentiate into macrophage and dendritic cell subsets and participate in tissue homeostasis, infection, autoimmune disease, and cancer. Enabling genome engineering in monocytes and their effector cells will facilitate a myriad of applications for basic and translational research. Here, we demonstrate that CRISPR-Cas9 RNPs can be used for efficient gene knockout in primary human monocytes. In addition, we demonstrate that intracellular RNases are likely responsible for poor and heterogenous mRNA expression as incorporation of pan-RNase inhibitor allows efficient genome engineering following mRNA-based delivery of Cas9 and base editor enzymes. Moreover, we demonstrate that CRISPR-Cas9 combined with an rAAV vector DNA donor template mediates site-specific insertion and expression of a transgene in primary human monocytes. Finally, we demonstrate that SIRPa knock-out monocyte-derived macrophages have enhanced activity against cancer cells, highlighting the potential for application in cellular immunotherapies. [ABSTRACT FROM AUTHOR]

Published
2022
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12. Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders.

Author

Laoharawee K, Kleinboehl EW, Jensen JD, Peterson JJ, Slipek NJ, Wick BJ, Johnson MJ, Webber BR, and Moriarity BS

Abstract

Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

Published
2024
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13. Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing.

Author

Wang M, Krueger JB, Gilkey AK, Stelljes EM, Kluesner MG, Pomeroy EJ, Skeate JG, Slipek NJ, Lahr WS, Vázquez PNC, Zhao Y, Eaton EJ, Laoharawee K, Webber BR, and Moriarity BS

Abstract

Natural killer (NK) cells' unique ability to kill transformed cells expressing stress ligands or lacking major histocompatibility complexes (MHC) has prompted their development for immunotherapy. However, NK cells have demonstrated only moderate responses against cancer in clinical trials and likely require advanced genome engineering to reach their full potential as a cancer therapeutic. Multiplex genome editing with CRISPR/Cas9 base editors (BE) has been used to enhance T cell function and has already entered clinical trials but has not been reported in human NK cells. Here, we report the first application of BE in primary NK cells to achieve both loss-of-function and gain-of-function mutations. We observed highly efficient single and multiplex base editing, resulting in significantly enhanced NK cell function. Next, we combined multiplex BE with non-viral TcBuster transposon-based integration to generate IL-15 armored CD19 CAR-NK cells with significantly improved functionality in a highly suppressive model of Burkitt's lymphoma both in vitro and in vivo . The use of concomitant non-viral transposon engineering with multiplex base editing thus represents a highly versatile and efficient platform to generate CAR-NK products for cell-based immunotherapy and affords the flexibility to tailor multiple gene edits to maximize the effectiveness of the therapy for the cancer type being treated., Competing Interests: Conflict of interest statement M.W., E.J.P., M.G.K., B.S.M. and B.R.W. have filed patents covering the methods and approaches outlined in this work.

Published
2024
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14. Implication of ZNF217 in Accelerating Tumor Development and Therapeutically Targeting ZNF217-Induced PI3K-AKT Signaling for the Treatment of Metastatic Osteosarcoma.

Author

Smeester BA, Draper GM, Slipek NJ, Larsson AT, Stratton N, Pomeroy EJ, Becklin KL, Yamamoto K, Williams KB, Laoharawee K, Peterson JJ, Abrahante JE, Rathe SK, Mills LJ, Crosby MR, Hudson WA, Rahrmann EP, Largaespada DA, and Moriarity BS

Subjects
Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Ectopic Gene Expression, Gene Amplification, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Models, Biological, Osteosarcoma drug therapy, Osteosarcoma etiology, Osteosarcoma metabolism, Osteosarcoma pathology, Trans-Activators metabolism, Xenograft Model Antitumor Assays, Biomarkers, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Trans-Activators genetics
Abstract

We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas using the Sleeping Beauty ( SB ) transposon system. Here, we followed up by investigating the genetic role of ZNF217 in osteosarcoma initiation and progression through the establishment of a novel genetically engineered mouse model, in vitro assays, orthotopic mouse studies, and paired these findings with preclinical studies using a small-molecule inhibitor. Throughout, we demonstrate that ZNF217 is coupled to numerous facets of osteosarcoma transformation, including proliferation, cell motility, and anchorage independent growth, and ultimately promoting osteosarcoma growth, progression, and metastasis in part through positive modulation of PI3K-AKT survival signaling. Pharmacologic blockade of AKT signaling with nucleoside analogue triciribine in ZNF217 + orthotopically injected osteosarcoma cell lines reduced tumor growth and metastasis. Our data demonstrate that triciribine treatment may be a relevant and efficacious therapeutic strategy for patients with osteosarcoma with ZNF217 + and p-AKT rich tumors. With the recent revitalization of triciribine for clinical studies in other solid cancers, our study provides a rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217 + osteosarcoma., (©2020 American Association for Cancer Research.)

Published
2020
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15. CRISPR/Cas9-Based Positive Screens for Cancer-Related Traits.

Author

Slipek NJ, Varshney J, and Largaespada DA

Subjects
Genome, Human, Humans, Neoplasm Proteins antagonists & inhibitors, Neoplasms pathology, CRISPR-Cas Systems, Genomics methods, Neoplasm Proteins genetics, Neoplasms genetics, Quantitative Trait Loci
Abstract

Since the advent of large-scale, detailed descriptive cancer genomics studies at the beginning of the century, such as The Cancer Genome Atlas (TCGA), labs around the world have been working to make this data useful. Data like these can be made more useful by comparison with complementary functional genomic data. One new example is the application of CRISPR/Cas9-based library screening for cancer-related traits in cell lines. Such screens can reveal genome-wide suppressors of tumorigenesis and metastasis. Here we describe the use of widely available lentiviral libraries for such screens in cultured cell lines.

Published
2019
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