Lentiviral vectors for precise expression to treat X-linked lymphoproliferative disease

被引：3

作者：

Ayoub, Paul G. ^{[1
]}

Gensheimer, Julia ^{[3
,7
]}

Lathrop, Lindsay ^{[1
]}

Juett, Colin ^{[2
]}

Quintos, Jason ^{[2
]}

Tam, Kevin ^{[2
]}

Reid, Jack ^{[2
]}

Ma, Feiyang ^{[2
]}

Tam, Curtis ^{[2
]}

McAuley, Grace E. ^{[2
]}

Brown, Devin ^{[2
]}

Wu, Xiaomeng ^{[2
]}

Zhang, Ruixue ^{[2
]}

Bradford, Kathryn ^{[3
]}

Hollis, Roger P. ^{[2
]}

Crooks, Gay M. ^{[3
,4
,5
,6
,7
]}

Kohn, Donald B. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Div Pediat Hematol Oncol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell R, Ctr Regenerat Med & Stem Cell Res, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

来源：

MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT | 2024年 / 32卷 / 04期

关键词：

T-CELLS; SAP; GENE; SAP/SH2D1A; MECHANISMS; SLAM; STEM; 2B4;

D O I：

10.1016/j.omtm.2024.101323

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

X-linked lymphoproliferative disease (XLP1) results from SH2D1A gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the SH2D1A gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP. We screened them for their on-target enhancer activity in T, NK, and NKT cells and their off-target enhancer activity in B cell and myeloid populations. In combination, three enhancer elements increased SAP promoter expression up to 4-fold in on-target populations in vitro. NSG-Tg(Hu-IL15) xenograft studies with XLPSMART LVs demonstrated up to 7-fold greater expression in on-target cells over a control EFS-LV, with no off-target expression. The XLP-SMART LVs exhibited stage-specific T and NK cell expression in peripheral blood, bone marrow, spleen, and thymic tissues (mimicking expression patterns of SAP). Transduction of XLP1 patient CD8+ T cells or BM CD34+ cells with and NK cytotoxicity to wild-type levels, respectively. These data demonstrate that it is feasible to create a lineage and stage-specific LV to restore the XLP1 phenotype by gene therapy.

引用

页数：18

共 57 条

[1] Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase [J].

Aoukaty, A ;

Tan, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (15) :13331-13337

[2] Enhanced development of functional human NK cells in NOD-scid-IL2rgnull mice expressing human IL15 [J].

Aryee, Ken-Edwin ;

Burzenski, Lisa M. ;

Yao, Li-Chin ;

Keck, James G. ;

Greiner, Dale L. ;

Shultz, Leonard D. ;

Brehm, Michael A. .

FASEB JOURNAL, 2022, 36 (09)

[3] X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease [J].

Booth, Claire ;

Gilmour, Kimberly C. ;

Veys, Paul ;

Gennery, Andrew R. ;

Slatter, Mary A. ;

Chapel, Helen ;

Heath, Paul T. ;

Steward, Colin G. ;

Smith, Owen ;

O'Meara, Anna ;

Kerrigan, Hilary ;

Mahlaoui, Nizar ;

Cavazzana-Calvo, Marina ;

Fischer, Alain ;

Moshous, Despina ;

Blanche, Stephane ;

Pachlopnick-Schmid, Jana ;

Latour, Sylvain ;

de Saint-Basile, Genevieve ;

Albert, Michael ;

Notheis, Gundula ;

Rieber, Nikolaus ;

Strahm, Brigitte ;

Ritterbusch, Henrike ;

Lankester, Arjan ;

Hartwig, Nico G. ;

Meyts, Isabelle ;

Plebani, Alessandro ;

Soresina, Annarosa ;

Finocchi, Andrea ;

Pignata, Claudio ;

Cirillo, Emilia ;

Bonanomi, Sonia ;

Peters, Christina ;

Kalwak, Krzysztof ;

Pasic, Srdjan ;

Sedlacek, Petr ;

Jazbec, Janez ;

Kanegane, Hirokazu ;

Nichols, Kim E. ;

Hanson, I. Celine ;

Kapoor, Neena ;

Haddad, Elie ;

Cowan, Morton ;

Choo, Sharon ;

Smart, Joanne ;

Arkwright, Peter D. ;

Gaspar, Hubert B. .

BLOOD, 2011, 117 (01) :53-62

[4] Parameters for establishing humanized mouse models to study human immunity: Analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rγnull mutation [J].

Brehm, Michael A. ;

Cuthbert, Amy ;

Yang, Chaoxing ;

Miller, David M. ;

Dilorio, Philip ;

Laning, Joseph ;

Burzenski, Lisa ;

Gott, Bruce ;

Foreman, Oded ;

Kavirayani, Anoop ;

Herlihy, Mary ;

Rossini, Aldo A. ;

Shultz, Leonard D. ;

Greiner, Dale L. .

CLINICAL IMMUNOLOGY, 2010, 135 (01) :84-98

[5] Induction of Chromosomal Translocations with CRISPR-Cas9 and Other Nucleases: Understanding the Repair Mechanisms That Give Rise to Translocations [J].

Brunet, Erika ;

Jasin, Maria .

CHROMOSOME TRANSLOCATION, 2018, 1044 :15-25

[6] Generalized DNA Barcode Design Based on Hamming Codes [J].

Bystrykh, Leonid V. .

PLOS ONE, 2012, 7 (05)

[7] Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation [J].

Catarino, Rui R. ;

Stark, Alexander .

GENES & DEVELOPMENT, 2018, 32 (3-4) :202-223

[8] Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene [J].

Coffey, AJ ;

Brooksbank, RA ;

Brandau, O ;

Oohashi, T ;

Howell, GR ;

Bye, JM ;

Cahn, AP ;

Durham, J ;

Heath, P ;

Wray, P ;

Pavitt, R ;

Wilkinson, J ;

Leversha, M ;

Huckle, E ;

Shaw-Smith, CJ ;

Dunham, A ;

Rhodes, S ;

Schuster, V ;

Porta, G ;

Yin, L ;

Serafini, P ;

Sylla, B ;

Zollo, M ;

Franco, B ;

Bolino, A ;

Seri, M ;

Lanyi, A ;

Davis, JR ;

Webster, D ;

Harris, A ;

Lenoir, G ;

St Basile, GD ;

Jones, A ;

Behloradsky, BH ;

Achatz, H ;

Murken, J ;

Fassler, R ;

Sumegi, J ;

Romeo, G ;

Vaudin, M ;

Ross, MT ;

Meindl, A ;

Bentley, DR .

NATURE GENETICS, 1998, 20 (02) :129-135

[9] Highly efficient large-scale lentiviral vector concentration by tandem tangential flow filtration [J].

Cooper, Aaron R. ;

Patel, Sanjeet ;

Senadheera, Shantha ;

Plath, Kathrin ;

Kohn, Donald B. ;

Hollis, Roger P. .

JOURNAL OF VIROLOGICAL METHODS, 2011, 177 (01) :1-9

[10] SAP is required for generating long-term humoral immunity [J].

Crotty, S ;

Kersh, EN ;

Cannons, J ;

Schwartzberg, PL ;

Ahmed, R .

NATURE, 2003, 421 (6920) :282-287

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