Dataset Information

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

ABSTRACT: Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p < 0.05) in the grafts. In addition, expression of adhesion molecules, cytokines, as well as numbers of proliferative SMCs, matrix metalloproteinase-9-positive cells, and inflammatory cell infiltration were significantly decreased in treated aortic grafts. Our findings demonstrate the feasibility, efficacy, and specificity of the anti-AP-1 RNA dON approach for the treatment of allograft vasculopathy in an animal model. Moreover, the AAV-based approach in general provides the possibility to achieve a prolonged delivery of nucleic-acids-based therapeutics in to the blood vessel wall.

SUBMITTER: Remes A

PROVIDER: S-EPMC6838891 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

Remes Anca A Franz Maximilian M Mohr Franziska F Weber Antje A Rapti Kleopatra K Jungmann Andreas A Karck Matthias M Hecker Markus M Kallenbach Klaus K Müller Oliver J OJ Arif Rawa R Wagner Andreas H AH

Molecular therapy. Methods & clinical development 20191002

Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleot ...[more]

PMID: 31720303

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Project description:BACKGROUND:BK Polyomavirus (BKPyV) causes premature graft failure in 1 to 15% of kidney transplant (KT) recipients. High-level BKPyV-viruria and BKPyV-DNAemia precede polyomavirus-associated nephropathy (PyVAN), and guide clinical management decisions. In most cases, BKPyV appears to come from the donor kidney, but data from biopsy-proven PyVAN cases are lacking. Here, we report the early fulminant course of biopsy-proven PyVAN in two male KT recipients in their sixties, receiving kidneys from the same deceased male donor. CASE PRESENTATIONS:Both recipients received intravenous basiliximab induction, and maintenance therapy consisting of tacrolimus (trough levels 3-7?ng/mL from time of engraftment), mycophenolate mofetil 750?mg bid, and prednisolone. At 4?weeks post-transplant, renal function was satisfactory with serum creatinine concentrations of 106 and 72??mol/L in recipient #1 and recipient #2, respectively. Plasma BKPyV-DNAemia was first investigated at 5 and 8?weeks post-transplant being 8.58?×?104 and 1.12?×?106 copies/mL in recipient #1 and recipient #2, respectively. Renal function declined and biopsy-proven PyVAN was diagnosed in both recipients at 12?weeks post-transplant. Mycophenolate mofetil levels were reduced from 750?mg to 250?mg bid while tacrolimus levels were kept below 5?ng/mL. Recipient #2 cleared BKPyV-DNAemia at 5.5?months post-transplant, while recipient #1 had persistent BKPyV-DNAemia of 1.07?×?105 copies/mL at the last follow-up 52?weeks post-transplant. DNA sequencing of viral DNA from early plasma samples revealed apparently identical viruses in both recipients, belonging to genotype Ib-2 with archetype non-coding control region. Retrospective serological work-up, demonstrated that the donor had high BKPyV-IgG-virus-like particle ELISA activity and a high BKPyV-genotype I neutralizing antibody titer, whereas both KT recipients only had low neutralizing antibody titers pre-transplantation. By 20?weeks post-transplant, the neutralizing antibody titer had increased by >?1000-fold in both recipients, but only recipient #2 cleared BKPyV-DNAemia. CONCLUSIONS:Low titers of genotype-specific neutralizing antibodies in recipients pre-transplant, may identify patients at high risk for early fulminant donor-derived BKPyV-DNAemia and PyVAN, but development of high neutralizing antibody titers may not be sufficient for clearance.

Dataset Information

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

Publications

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

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