| 1. |
|
|
| 2. |
- Anttila, V., et al.
(författare)
-
Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
-
Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool. © 2022
|
|
| 3. |
- Baum, C, et al.
(författare)
-
Chance or necessity? Insertional mutagenesis in gene therapy and its consequences
- 2004
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 9:1, s. 5-13
-
Forskningsöversikt (refereegranskat)abstract
- Recently, unusual forms of leukemias have developed as complications following retroviral transfer of potentially therapeutic genes into hematopoietic cells. A crucial component in the pathogenesis of these complications was the upregulation of a cellular proto-oncogene by random insertion of the retroviral gene transfer vector. These findings have great implications for the genetic manipulation of somatic stem cells in medicine. This review discusses the extent to which the random oncogene activation may have required disease-specific stimuli of the transgene and the hematopoietic milieu to become leukemogenic. Based on these considerations, we propose approaches to risk prediction and prevention.
|
|
| 4. |
|
|
| 5. |
- Bexell, Daniel, et al.
(författare)
-
Bone Marrow Multipotent Mesenchymal Stroma Cells Act as Pericyte-like Migratory Vehicles in Experimental Gliomas.
- 2009
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 2008:Nov 4., s. 183-190
-
Tidskriftsartikel (refereegranskat)abstract
- Bone marrow-derived multipotent mesenchymal stroma cells (MSCs) have emerged as cellular vectors for gene therapy of solid cancers. We implanted enhanced green fluorescent protein-expressing rat MSCs directly into rat malignant gliomas to address their migratory capacity, phenotype, and effects on tumor neovascularization and animal survival. A single intratumoral injection of MSCs infiltrated the majority of invasive glioma extensions (72 +/- 14%) and a substantial fraction of distant tumor microsatellites (32 +/- 6%). MSC migration was highly specific for tumor tissue. Grafted MSCs integrated into tumor vessel walls and expressed pericyte markers alpha-smooth muscle actin, neuron-glia 2, and platelet-derived growth factor receptor-beta but not endothelial cell markers. The pericyte marker expression profile and perivascular location of grafted MSCs indicate that these cells act as pericytes within tumors. MSC grafting did not influence tumor microvessel density or survival of tumor-bearing animals. The antiangiogenic drug Sunitinib markedly reduced the numbers of grafted MSCs migrating within tumors. We found no MSCs within gliomas following intravenous (i.v.) injections. Thus, MSCs should be administered by intratumoral implantations rather than by i.v. injections. Intratumorally grafted pericyte-like MSCs might represent a particularly well-suited vector system for delivering molecules to affect tumor angiogenesis and for targeting cancer stem cells within the perivascular niche.Molecular Therapy (2008); doi:10.1038/mt.2008.229.
|
|
| 6. |
- Bexell, Daniel, et al.
(författare)
-
Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors.
- 2010
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; May 4, s. 1067-1075
-
Tidskriftsartikel (refereegranskat)abstract
- Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for their use as a gene vector system in neoplasms. Here, we review the tumor-directed migratory potential of MSCs, mechanisms of the migration, and the choice of therapeutic transgenes, with a focus on malignant gliomas as a model system for invasive and highly vascularized tumors. We examine recent findings demonstrating that MSCs share many characteristics with pericytes and that implanted MSCs localize primarily to perivascular niches within tumors, which might have therapeutic implications. The use of MSC vectors in cancer gene therapy raises concerns, however, including a possible MSC contribution to tumor stroma and vasculature, MSC-mediated antitumor immune suppression, and the potential malignant transformation of cultured MSCs. Nonetheless, we highlight the novel prospects of MSC-based tumor therapy, which appears to be a promising approach.
|
|
| 7. |
|
|
| 8. |
- Cederfjäll, Erik, et al.
(författare)
-
Controlled striatal DOPA production from a gene delivery system in a rodent model of Parkinson's disease.
- 2015
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 23:5, s. 896-906
-
Tidskriftsartikel (refereegranskat)abstract
- Conventional symptomatic treatment for Parkinson's disease (PD) with long term L-DOPA is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally coupled GCH1 enzyme (DD-GCH1) while the TH enzyme was constitutively expressed, packaged in adeno-associated viral (AAV) vectors. Expression of DD-GCH1 was regulated by the activating ligand trimethoprim (TMP) that crosses the blood-brain barrier. We show that the resulting intervention provides a TMP-dose dependent regulation of DOPA synthesis that is closely linked to the magnitude of functional effects. Our data constitutes the first proof of principle for controlled reconstitution of dopamine capacity in the brain and suggests that such next generation gene therapy strategies are now mature for pre-clinical development towards use in patients with PD.Molecular Therapy (2015); doi:10.1038/mt.2015.8.
|
|
| 9. |
- Cederfjäll, Erik, et al.
(författare)
-
Design of a Single AAV Vector for Coexpression of TH and GCH1 to Establish Continuous DOPA Synthesis in a Rat Model of Parkinson's Disease.
- 2012
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 20:7, s. 1315-1326
-
Tidskriftsartikel (refereegranskat)abstract
- Preclinical efficacy of continuous delivery of 3,4-dihydroxyphenylalanine (DOPA) with adeno-associated viral (AAV) vectors has recently been documented in animal models of Parkinson's disease (PD). So far, all studies have utilized a mix of two monocistronic vectors expressing either of the two genes, tyrosine hydroxylase (TH) and GTP cyclohydrolase-1 (GCH1), needed for DOPA production. Here, we present a novel vector design that enables efficient DOPA production from a single AAV vector in rats with complete unilateral dopamine (DA) lesions. Functional efficacy was assessed with drug-induced and spontaneous motor behavioral tests where vector-treated animals showed near complete and stable recovery within 1 month. Recovery of motor function was associated with restoration of extracellular DA levels as assessed by online microdialysis. Histological analysis showed robust transgene expression not only in the striatum but also in overlying cortical areas. In globus pallidus, we noted loss of NeuN staining, which might be due to different sensitivity in neuronal populations to transgene expression. Taken together, we present a single AAV vector design that result in efficient DOPA production and wide-spread transduction. This is a favorable starting point for continued translation toward a therapeutic application, although future studies need to carefully review target region, vector spread and dilution with this approach.
|
|
| 10. |
- Cheng, Wing-Shing, et al.
(författare)
-
A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer
- 2004
-
Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 10:2, s. 355-364
-
Tidskriftsartikel (refereegranskat)abstract
- TARP (T cell receptor gamma-chain alternate reading frame protein) is a protein that in males is uniquely expressed in prostate epithelial cells and prostate cancer cells. We have previously shown that the transcriptional activity of a chimeric sequence comprising the TARP promoter (TARPp) and the PSA enhancer (PSAe) is strictly controlled by testosterone and highly restricted to cells of prostate origin. Here we report that a chimeric sequence comprising TARPp and the PSMA enhancer (PSMAe) is highly active in testosterone-deprived prostate cancer cells, while a regulatory sequence comprising PSAe, PSMAe, and TARPp (PPT) has high prostate-specific activity both in the presence and in the absence of testosterone. Therefore, the PPT sequence may, in a gene therapy setting, be beneficial to prostate cancer patients that have been treated with androgen withdrawal. A recombinant adenovirus vector with the PPT sequence, shielded from interfering adenoviral sequences by the mouse H19 insulator, yields high and prostate-specific transgene expression both in cell cultures and when prostate cancer, PC-346C, tumors were grown orthotopically in nude mice. Intravenous virus administration reveals both higher activity and higher selectivity for the insulator-shielded PPT sequence than for the immediate-early CMV promoter. Therefore, we believe that an adenovirus with therapeutic gene expression controlled by an insulator-shielded PPT sequence is a promising candidate for gene therapy of prostate cancer.
|
|
