RNA-based therapies by microRNA restoration and circular RNA targeting for T-cell chronic lymphoproliferative disorders

PI:

Stefania Bortoluzzi

Email:

stefania.bortoluzzi@unipd.it

Affiliation:

University of Padova

ORCID:

0000-0001-8240-3070

T large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disease whose pathogenesis is still not completely understood and for which a curative therapy is missing. The course of the disease is chronic with cytopenias, particularly neutropenia, being the clinical manifestations most impacting the patient quality of life and survival.
Recent high-throughput miRNome analyses linked STAT3 activation, one of the key hallmarks of T-LGLL, to aberrant expression of specific miRNAs, which contribute to the disease pathogenesis. We demonstrated that miR-146b deletion plays a direct role in the development of neutropenia, providing the proof of principle demonstration that miR-146b restoration can be an effective RNA-based therapeutic approach. In this project, by deep transcriptomic and proteomic analyses, we are investigating miR-146b restoration effects in leukemic T-LGL, to fully elucidate its involvement in leukemia development. In parallel, we are designing  new strategies for miRNA effective intracellular delivery using engineered lipoplexes, with efficacy tests in ex-vivo leukemic T-LGL. Next, the biosafety of miRNAs restoration in vivo and of the developed carrier, will be evaluated. 
The project will lead to the development of a miRNA restoration therapy for T-GLL, an orphan disease, as well as valuable technical advances in the generation of selective and efficient targeted nanocarriers functionalized with novel condensing agents for therapeutic nucleic acids, with broader applications in other clinical settings.

Relevant Publications
2023

  1.  Malfanti A, Sami H. Balasso A, Marostica G, Arpac B, Mastrotto F, Mantovani G, Cola E, Anton M, Caliceti P, Ogris M, Salmaso S. Subtle control of cell penetration enhancer shielding and endosomal escape-kinetics crucial for efficient and biocompatible siRNA delivery. JOURNAL OF CONTROLLED RELEASE, 2023 Sep 16;S0168-3659(23)00610-7. doi: 10.1016/j.jconrel.2023.09.022. Online ahead of print.

  2. Vicenzetto C, Gasparini VR, Barilà G, Semenzato G, Teramo A, Calabretto G, Rampazzo E, Carraro S, Trimarco V, Trentin L, Facco M, Semenzato G, Zambello R. Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia. HAEMATOLOGICA. 2023 Jul 13. Online ahead of print. doi: 10.3324/haematol.2022.282306. 

  3. Garbin A, Contarini G, Damanti CC, Tosato A, Bortoluzzi S, Gaffo E, Pizzi M, Carraro E, Lo Nigro L, Vinti L, Pillon M, Biffi A, Lovisa F, Mussolin L. BIOCHEM PHARMACOL. MiR-146a-5p enrichment in small-extracellular vesicles of relapsed pediatric ALCL patients promotes macrophages infiltration and differentiation. 2023 Aug 15;215:115747. doi: 10.1016/j.bcp.2023.115747.

  4. Damanti CC, Ferrone L, Gaffo E, Garbin A, Tosato A, Contarini G, Gallingani I, Angioni R, Molon B, Borile G, Carraro E, Pillon M, Scarmozzino F, Dei Tos AP, Pizzi M, Ciscato F, Rasola A, Biffi A, Bortoluzzi S, Lovisa F, Mussolin L. Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric anaplastic large-cell lymphoma. CANCER COMMUN (Lond). 2023 May;43(5):630-634. doi: 10.1002/cac2.12415

  5. Semenzato G, Calabretto G, Barilà G, Gasparini VR, Teramo A, Zambello R. Not all LGL leukemias are created equal. BLOOD REV. 2023 Feb 20:101058.

  6. Barilà G, Grassi A, Cheon H, Teramo A, Calabretto G, Chahal J, Vicenzetto C, Almeida J, Shemo BC, Shi M, Gasparini VR, Munoz-Garcia N, Pastoret C, Nakazawa H, Oshimi K, Sokol L, Ishida F, Lamy T, Orfao A, Morice WG, Loughran TP, Semenzato G, Zambello R. Tγδ LGLL identifies a subset with more symptomatic disease: analysis of an international cohort of 137 patients. BLOOD. 2023 Mar 2;141(9):1036-1046.

  7. Barilà G, Quaglia FM, Furlan A, Pescosta N, Bonalumi A, Marcon C, Pascarella A, Tinelli M, De March E, Lico A, Sartori R, Clissa C, De Sabbata G, Nappi D, Porrazzo M, De Marchi R, Pavan L, Tosetto A, Gherlinzoni F, Krampera M, Bassan R, Patriarca F, Semenzato G, Zambello R. A real-life study of daratumumab-bortezomib-dexamethasone (D-VD) in lenalidomide exposed/refractory multiple myeloma patients: a report from the Triveneto Myeloma Working Group. ANN HEMATOL. 2023 Sep 20. doi: 10.1007/s00277-023-05443-8. Online ahead of print.

  8. Barilà G, Crimì F, Arangio Febbo M, Pavan L, Vedovato S, Cabrelle G, Zanon C, Campi C, Cecchin D, Zucchetta P, Lacognata C, Semenzato G, Zambello R. Imaging minimal residual disease evaluation in multiple myeloma using [18F]FDG PET/MRI. LEUK LYMPHOMA. 2023 Feb;64(2):503-506. doi: 10.1080/10428194.2022.2142053.

2022

  1. Teramo A, Binatti A, Ciabatti E, Schiavoni G, Tarrini G, Barilà G, Calabretto G, Vicenzetto C, Gasparini VR, Facco M, Petrini I, Grossi R, Pisanti N, Bortoluzzi S, Falini B, Tiacci E, Galimberti S, Semenzato G, Zambello R.  Defining TCRγδ lymphoproliferative disorders by combined immunophenotypic and molecular evaluation. Nat Commun. 2022 Jun 8;13(1):3298. doi: 10.1038/s41467-022-31015-x.



  2. Huuhtanen J, Bhattacharya D, Lönnberg T, Kankainen M, Kerr C, Theodoropoulos J, Rajala H, Gurnari C, Kasanen T, Braun T, Teramo A, Zambello R, Herling M, Ishida F, Kawakami T, Salmi M, Loughran T, Maciejewski JP, Lähdesmäki H, Kelkka T, Mustjoki S.Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia. NAT COMMUN. 2022 Apr 11;13(1):1981. doi: 10.1038/s41467-022-29173-z. PMID: 35411050 Free PMC article.



  3. Bhattacharya D, Teramo A, Gasparini VR, Huuhtanen J, Kim D, Theodoropoulos J, Schiavoni G, Barilà G, Vicenzetto C, Calabretto G, Facco M, Kawakami T, Nakazawa H, Falini B, Tiacci E, Ishida F, Semenzato G, Kelkka T, Zambello R, Mustjoki S.  Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia. BLOOD CANCER J. 2022 Feb 24;12(2):31. doi: 10.1038/s41408-022-00630-8.



  4. Mastrotto F, Pirazzini M, Negro S, Salama A, Martinez-Pomares L, Mantovani G.  Sulfation at Glycopolymer Side Chains Switches Activity at the Macrophage Mannose Receptor (CD206) In Vitro and In Vivo. J AM CHEM SOC. 2022 Dec 21;144(50):23134-23147. doi: 10.1021/jacs.2c10757.



  5. Bellato F, Feola S, Dalla Verde G, Bellio G, Pirazzini M, Salmaso S, Caliceti P, Cerullo V, Mastrotto F. Mannosylated Polycations Target CD206+ Antigen-Presenting Cells and Mediate T-Cell-Specific Activation in Cancer Vaccination.BIOMACROMOLECULES. 2022 Dec 12;23(12):5148-5163. doi: 10.1021/acs.biomac.2c00993.

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