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14 results on '"Mendel, Matthew"'

3. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease

Author

Zeitler, Bryan, Froelich, Steven, Marlen, Kimberly, Shivak, David A, Yu, Qi, Li, Davis, Pearl, Jocelynn R, Miller, Jeffrey C, Zhang, Lei, Paschon, David E, Hinkley, Sarah J, Ankoudinova, Irina, Lam, Stephen, Guschin, Dmitry, Kopan, Lexi, Cherone, Jennifer M, Nguyen, Hoang-Oanh B, Qiao, Guijuan, Ataei, Yasaman, Mendel, Matthew C, Amora, Rainier, Surosky, Richard, Laganiere, Josee, Vu, B Joseph, Narayanan, Anand, Sedaghat, Yalda, Tillack, Karsten, Thiede, Christina, Gärtner, Annette, Kwak, Seung, Bard, Jonathan, Mrzljak, Ladislav, Park, Larry, Heikkinen, Taneli, Lehtimäki, Kimmo K, Svedberg, Marie M, Häggkvist, Jenny, Tari, Lenke, Tóth, Miklós, Varrone, Andrea, Halldin, Christer, Kudwa, Andrea E, Ramboz, Sylvie, Day, Michelle, Kondapalli, Jyothisri, Surmeier, D James, Urnov, Fyodor D, Gregory, Philip D, Rebar, Edward J, Muñoz-Sanjuán, Ignacio, and Zhang, H Steve

Published
2019
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4. Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human α1-antitrypsin deficiency

Author

Li, Yanfeng, primary, Guha, Chandan, additional, Asp, Patrik, additional, Wang, Xia, additional, Tchaikovskya, Tatyana L., additional, Kim, Kenneth, additional, Mendel, Matthew, additional, Cost, Gregory J., additional, Perlmutter, David H., additional, Roy-Chowdhury, Namita, additional, Fox, Ira J., additional, Conway, Anthony, additional, and Roy-Chowdhury, Jayanta, additional

Published
2023
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5. Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma

Author

Beane, Joal D, Lee, Gary, Zheng, Zhili, Mendel, Matthew, Abate-Daga, Daniel, Bharathan, Mini, Black, Mary, Gandhi, Nimisha, Yu, Zhiya, Chandran, Smita, Giedlin, Martin, Ando, Dale, Miller, Jeff, Paschon, David, Guschin, Dmitry, Rebar, Edward J, Reik, Andreas, Holmes, Michael C, Gregory, Philip D, Restifo, Nicholas P, Rosenberg, Steven A, Morgan, Richard A, and Feldman, Steven A

Published
2015
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6. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells

Author

Hoban, Megan D., Cost, Gregory J., Mendel, Matthew C., Romero, Zulema, Kaufman, Michael L., Joglekar, Alok V., Ho, Michelle, Lumaquin, Dianne, Gray, David, Lill, Georgia R., Cooper, Aaron R., Urbinati, Fabrizia, Senadheera, Shantha, Zhu, Allen, Liu, Pei-Qi, Paschon, David E., Zhang, Lei, Rebar, Edward J., Wilber, Andrew, Wang, Xiaoyan, Gregory, Philip D., Holmes, Michael C., Reik, Andreas, Hollis, Roger P., and Kohn, Donald B.

Published
2015
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7. Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma

Author

Brown, Christine E, Rodriguez, Analiz, Palmer, Joycelynne, Ostberg, Julie R, Naranjo, Araceli, Wagner, Jamie R, Aguilar, Brenda, Starr, Renate, Weng, Lihong, Synold, Timothy W, Tran, Vivi, Wang, Shelley, Reik, Andreas, D’Apuzzo, Massimo, Ressler, Julie A, Zhou, Yuanyue, Mendel, Matthew, Gregory, Philip D, Holmes, Michael C, Tang, Winson W, Forman, Stephen J, Jensen, Michael C, and Badie, Behnam

Subjects
Cancer Research, Oncology, T-Lymphocytes, Clinical Investigations, Interleukin-13 Receptor alpha2 Subunit, Humans, Steroids, Neurology (clinical), Glioblastoma, Glucocorticoids, Immunotherapy, Adoptive, Xenograft Model Antitumor Assays, Dexamethasone
Abstract

Background Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach. Methods We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day). Results The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500–5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects. Conclusions This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.

Published
2022
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8. Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human α1-antitrypsin deficiency.

Author

Yanfeng Li, Guha, Chandan, Asp, Patrik, Xia Wang, Tchaikovskya, Tatyana L., Kim, Kenneth, Mendel, Matthew, Cost, Gregory J., Perlmutter, David H., Roy-Chowdhury, Namita, Fox, Ira J., Conway, Anthony, and Roy-Chowdhury, Jayanta

Subjects
HEPATIC fibrosis, GENOME editing, LABORATORY mice, ANIMAL disease models, RECOMBINANT viruses, HIGH cholesterol diet, GENE targeting
Abstract

Background: α1-antitrypsin deficiency is most commonly caused by a mutation in exon-7 of SERPINA1 (SA1-ATZ), resulting in hepatocellular accumulation of a misfolded variant (ATZ). Human SA1-ATZ-transgenic (PiZ) mice exhibit hepatocellular ATZ accumulation and liver fibrosis. We hypothesized that disrupting the SA1-ATZ transgene in PiZ mice by in vivo genome editing would confer a proliferative advantage to the genome-edited hepatocytes, enabling them to repopulate the liver. Methods: To create a targeted DNA break in exon-7 of the SA1-ATZ transgene, we generated 2 recombinant adeno-associated viruses (rAAV) expressing a zinc-finger nuclease pair (rAAV-ZFN), and another rAAV for gene correction by targeted insertion (rAAV-TI). PiZmice were injected i.v. with rAAV-TI alone or the rAAV-ZFNs at a low (7.5 x 1010vg/mouse, LD) or a high dose (1.5x1011vg/mouse, HD), with or without rAAV-TI. Two weeks and 6 months after treatment, livers were harvested for molecular, histological, and biochemical analyses. Results: Two weeks after treatment, deep sequencing of the hepatic SA1-ATZ transgene pool showed 6%±3% or 15%±4% nonhomologous end joining in mice receiving LD or HD rAAV-ZFN, respectively, which increased to 36%±12% and 36%±12%, respectively, 6 months after treatment. Two weeks postinjection of rAAV-TI with LD or HD of rAAV-ZFN, repair by targeted insertion occurred in 0.10%±0.09% and 0.25%±0.14% of SA1-ATZ transgenes, respectively, which increased to 5.2%±5.0% and 33%±13%, respectively, 6 months after treatment. Six months after rAAV-ZFN administration, there was a marked clearance of ATZ globules from hepatocytes, and resolution of liver fibrosis, along with reduction of hepatic TAZ/WWTR1, hedgehog ligands, Gli2, a TIMP, and collagen content. Conclusions: ZFN-mediated SA1-ATZ transgene disruption provides a proliferative advantage to ATZ-depleted hepatocytes, enabling them to repopulate the liver and reverse hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Published
2023
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11. Allele-selective transcriptional repression of mutant HTTfor the treatment of Huntington’s disease

Author

Zeitler, Bryan, Froelich, Steven, Marlen, Kimberly, Shivak, David A, Yu, Qi, Li, Davis, Pearl, Jocelynn R, Miller, Jeffrey C, Zhang, Lei, Paschon, David E, Hinkley, Sarah J, Ankoudinova, Irina, Lam, Stephen, Guschin, Dmitry, Kopan, Lexi, Cherone, Jennifer M, Nguyen, Hoang-Oanh B, Qiao, Guijuan, Ataei, Yasaman, Mendel, Matthew C, Amora, Rainier, Surosky, Richard, Laganiere, Josee, Vu, B Joseph, Narayanan, Anand, Sedaghat, Yalda, Tillack, Karsten, Thiede, Christina, Gärtner, Annette, Kwak, Seung, Bard, Jonathan, Mrzljak, Ladislav, Park, Larry, Heikkinen, Taneli, Lehtimäki, Kimmo K, Svedberg, Marie M, Häggkvist, Jenny, Tari, Lenke, Tóth, Miklós, Varrone, Andrea, Halldin, Christer, Kudwa, Andrea E, Ramboz, Sylvie, Day, Michelle, Kondapalli, Jyothisri, Surmeier, D James, Urnov, Fyodor D, Gregory, Philip D, Rebar, Edward J, Muñoz-Sanjuán, Ignacio, and Zhang, H Steve

Abstract

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtingene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.

Published
2019
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12. Non-viral Delivery of Zinc Finger Nuclease mRNA Enables Highly Efficient In VivoGenome Editing of Multiple Therapeutic Gene Targets

Author

Conway, Anthony, Mendel, Matthew, Kim, Kenneth, McGovern, Kyle, Boyko, Alisa, Zhang, Lei, Miller, Jeffrey C., DeKelver, Russell C., Paschon, David E., Mui, Barbara L., Lin, Paulo J.C., Tam, Ying K., Barbosa, Chris, Redelmeier, Tom, Holmes, Michael C., and Lee, Gary

Abstract

It has previously been shown that engineered zinc finger nucleases (ZFNs) can be packaged into adeno-associated viruses (AAVs) and delivered intravenously into mice, non-human primates, and most recently, humans to induce highly efficient therapeutic genome editing in the liver. Lipid nanoparticles (LNPs) are synthetic delivery vehicles that enable repeat administration and are not limited by the presence of preexisting neutralizing antibodies in patients. Here, we show that mRNA encoding ZFNs formulated into LNP can enable >90% knockout of gene expression in mice by targeting the TTRor PCSK9gene, at mRNA doses 10-fold lower than has ever been reported. Additionally, co-delivering mRNA-LNP containing ZFNs targeted to intron 1 of the ALBlocus with AAV packaged with a promoterless human IDSor FIXtherapeutic transgene can result in high levels of targeted integration and subsequent therapeutically relevant levels of protein expression in mice. Finally, we show repeat administration of ZFN mRNA-LNP after a single AAV donor dose results in significantly increased levels of genome editing and transgene expression compared to a single dose. These results demonstrate LNP-mediated ZFN mRNA delivery can drive highly efficient levels of in vivogenome editing and can potentially offer a new treatment modality for a variety of diseases.

Published
2019
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13. 77. Clinical Scale Zinc Finger Nuclease (ZFN)-Driven Gene-Editing of PD-1 in Tumor Infiltrating Lymphocytes (TIL) for the Potential Treatment of Metastatic Melanoma

Author

Beane, Joal D., primary, Lee, Gary, additional, Zheng, Zhili, additional, Gandhi, Nimisha, additional, Abate-Daga, Daniel, additional, Bharathan, Mini, additional, Black, Mary, additional, Mendel, Matthew, additional, Yu, Zhiya, additional, Kassim, Sadik H., additional, Chandran, Smita, additional, Giedlin, Martin A., additional, Ando, Dale, additional, Rebar, Ed, additional, Reik, Andreas, additional, Holmes, Michael C., additional, Gregory, Philip D., additional, Restifo, Nicholas P., additional, Rosenberg, Steven A., additional, Morgan, Richard A., additional, and Feldman, Steven A., additional

Published
2015
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14. 115. Correction of the Sickle-Cell Disease Mutation in Human Hematopoietic Stem/Progenitor Cells

Author

Hoban, Megan D., primary, Mendel, Matthew C., additional, Romero, Zulema, additional, Kaufman, Michael L., additional, Joglekar, Alok V., additional, Ho, Michelle, additional, Lumaquin, Dianne, additional, Gray, David, additional, Lill, Georgia R., additional, Cooper, Aaron R., additional, Urbinati, Fabrizia, additional, Senadheera, Shantha, additional, Zhu, Allen, additional, Liu, Pei-Qi, additional, Paschon, David E., additional, Zhang, Lei, additional, Rebar, Edward J., additional, Wilber, Andrew, additional, Wang, Xiaoyan, additional, Gregory, Philip D., additional, Holmes, Michael C., additional, Reik, Andreas, additional, Hollis, Roger P., additional, Kohn, Donald B., additional, and Cost, Gregory J., additional

Published
2015
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