| 1. |
- Foo, Kylie S, et al.
(author)
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Human ISL1+ ventricular progenitors self-assemble into an in vivo functional heart patch and preserve cardiac function post infarction
- 2018
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In: Molecular Therapy. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 1525-0016. ; 26:7, s. 1644-1659
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Journal article (peer-reviewed)abstract
- The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm x 3 mm x 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy. Correction in Mol Ther. 2021 Jan 6;29(1):409, DOI: 10.1016/j.ymthe.2020.11.015
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| 2. |
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Anttila, V., et al.
(author)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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In: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Journal article (peer-reviewed)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
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| 7. |
- Baum, C, et al.
(author)
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Chance or necessity? Insertional mutagenesis in gene therapy and its consequences
- 2004
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 9:1, s. 5-13
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Research review (peer-reviewed)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.
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| 8. |
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| 9. |
- Bexell, Daniel, et al.
(author)
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Bone Marrow Multipotent Mesenchymal Stroma Cells Act as Pericyte-like Migratory Vehicles in Experimental Gliomas.
- 2009
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 2008:Nov 4., s. 183-190
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Journal article (peer-reviewed)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.
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| 10. |
- Bexell, Daniel, et al.
(author)
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Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors.
- 2010
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; May 4, s. 1067-1075
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Journal article (peer-reviewed)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.
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| 11. |
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| 12. |
- Cederfjäll, Erik, et al.
(author)
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Controlled striatal DOPA production from a gene delivery system in a rodent model of Parkinson's disease.
- 2015
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 23:5, s. 896-906
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Journal article (peer-reviewed)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.
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| 13. |
- Cederfjäll, Erik, et al.
(author)
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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
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 20:7, s. 1315-1326
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Journal article (peer-reviewed)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.
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| 14. |
- Cheng, Wing-Shing, et al.
(author)
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A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer
- 2004
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In: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 10:2, s. 355-364
-
Journal article (peer-reviewed)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.
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| 15. |
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| 16. |
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| 17. |
- Dahl, Maria, et al.
(author)
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Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice
- 2015
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In: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 23:5, s. 835-844
-
Journal article (peer-reviewed)abstract
- Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase beta-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.
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| 18. |
- Dassie, Justin P., et al.
(author)
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Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen
- 2014
-
In: Molecular Therapy. - : Nature Publishing Group. - 1525-0016 .- 1525-0024. ; 22:11, s. 1910-1922
-
Journal article (peer-reviewed)abstract
- Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC. © The American Society of Gene amp; Cell Therapy.
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| 19. |
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| 20. |
- Dodiya, Hemraj B., et al.
(author)
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Differential Transduction Following Basal Ganglia Administration of Distinct Pseudotyped AAV Capsid Serotypes in Nonhuman Primates
- 2010
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 18:3, s. 579-587
-
Journal article (peer-reviewed)abstract
- We examined the transduction efficiency of different adeno-associated virus (AAV) capsid serotypes encoding for green fluorescent protein (GFP) flanked by AAV2 inverted terminal repeats in the nonhuman primate basal ganglia as a prelude to translational studies, as well as clinical trials in patients with Parkinson's disease (PD). Six intact young adult cynomolgus monkeys received a single 10 mu l injection of AAV2/1-GFP, AAV2/5-GFP, or AAV2/8-GFP pseudotyped vectors into the caudate nucleus and putamen bilaterally in a pattern that resulted in each capsid serotype being injected into at least four striatal sites. GFP immunohistochemistry revealed excellent transduction rates for each AAV pseudotype. Stereological estimates of GFP(+) cells within the striatum revealed that AAV2/5-GFP transduces significantly higher number of cells than AAV2/8-GFP (P < 0.05) and there was no significant difference between AAV2/5-GFP and AAV2/1-GFP (P = 0.348). Consistent with this result, Cavalieri estimates revealed that AAV2/5-GFP resulted in a significantly larger transduction volume than AAV2/8-GFP (P < 0.05). Each pseudotype transduced striatal neurons effectively [>95% GFP(+) cells colocalized neuron-specific nuclear protein (NeuN)]. The current data suggest that AAV2/5 and AAV2/1 are superior to AAV2/8 for gene delivery to the nonhuman primate striatum and therefore better candidates for therapeutic applications targeting this structure.
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| 21. |
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| 22. |
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| 23. |
- EL Andaloussi, Samir, et al.
(author)
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A novel cell-penetrating peptide, M918, for efficient delivery of proteins and peptide nucleic acids
- 2007
-
In: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 15:10, s. 1820-1826
-
Journal article (peer-reviewed)abstract
- Cell-penetrating peptides (CPPs) have attracted increasing attention in the past decade as a result of their high potential to convey various, otherwise impermeable, bioactive agents across cellular plasma membranes. Albeit different CPPs have proven potent in delivery of different cargoes, there is generally a correlation between high efficacy and cytotoxicity for these peptides. Hence, it is of great importance to find new, non-toxic CPPs with more widespread delivery properties. We present a novel CPP, M918, that efficiently translocates various cells in a non-toxic fashion. In line with most other CPPs, the peptide is internalized mainly via endocytosis, and in particular macropinocytosis, but independent of glycosaminoglycans on the cell surface. In addition, in a splice correction assay using antisense peptide nucleic acid (PNA) conjugated via a disulphide bridge to M918 (M918-PNA), we observed a dose-dependent increase in correct splicing, exceeding the effect of other CPPs. Our data demonstrate that M918 is a novel CPP that can be used to translocate different cargoes inside various cells efficiently.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Faustini, Gaia, et al.
(author)
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Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinsons disease-like phenotype
- 2022
-
In: Molecular Therapy. - : Cell Press. - 1525-0016 .- 1525-0024. ; 30:4, s. 1465-1483
-
Journal article (peer-reviewed)abstract
- Fibrillary aggregated alpha-synuclein (alpha-syn) deposition in Lewy bodies (LB) characterizes Parkinsons disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with alpha-syn to regulate dopamine (DA) release and can be found in the insoluble alpha-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human alpha-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates alpha-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human alpha-syn transgenic mice at PD-like stage with advanced alpha-syn aggregation and overt striatal synaptic failure, we could lower alpha-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates alpha-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.
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| 28. |
- Gjertsson, Inger, 1962, et al.
(author)
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Tolerance induction using lentiviral gene delivery delays onset and severity of collagen II arthritis.
- 2009
-
In: Molecular therapy : the journal of the American Society of Gene Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 17:4, s. 632-40
-
Journal article (peer-reviewed)abstract
- The treatment of rheumatoid arthritis remains suboptimal; thus there is considerable interest in the development of strategies that mediate tolerance to autoantigens. Using lentiviral gene transfer in vivo, we expressed the immunodominant epitope of collagen type II (CII) on major histocompatibility complex class II molecules (MHC II) in a mouse model of destructive arthritis. A sequence corresponding to amino acids 259-270 of CII was fused into the class II-associated invariant chain peptide (CLIP) position of the invariant chain to achieve efficient binding to MHC II. Transduction of cloned cells and primary antigen-presenting cells (APCs) in vitro demonstrated successful presentation of the peptide on MHC II, and a physiological glycosylation pattern. Compared with controls, mice intravenously injected with lentiviral vectors encoding this epitope displayed significantly less frequent, less severe, and less destructive arthritis, decreased lymphocyte proliferation in response to restimulation with CII, and lower CII-specific antibody levels. This was associated with an increased production of transforming growth factor-beta (TGF-beta) in vitro. We suggest that overexpression of the immunodominant CII epitope on MHC II induces T cell production of TGF-beta and leads to inhibition of arthritis by means of both antigen-specific and bystander mechanisms. Thus, antigen-specific tolerance induction using lentiviral gene delivery can ameliorate arthritis.
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| 29. |
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| 31. |
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| 32. |
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| 33. |
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| 34. |
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| 35. |
- Hu, Li-Peng, et al.
(author)
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Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression
- 2022
-
In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 30:10, s. 3284-3299
-
Journal article (peer-reviewed)abstract
- Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by terbinafine, an approved antifungal drug, might inhibit the development of CRC. A population-based study from Sweden identified a total of 185 patients who received terbinafine after their CRC diagnosis and found that they had a decreased risk of death (hazard ratio=0.50) and metastasis (hazard ratio=0.44) compared with patients without terbinafine administration. In multiple mouse models of CRC, administration of terbinafine decreased the fungal load, the fungus-induced myeloid-derived suppressor cell (MDSC) expansion, and the tumor burden. Fecal microbiota transplantation from mice without terbinafine treatment reversed MDSC infiltration and partially restored tumor proliferation. Mechanistically, terbinafine directly impaired tumor cell proliferation by reducing the ratio of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), suppressing the activity of glucose-6-phosphate dehydrogenase (G6PD), resulting in nucleotide synthesis disruption, deoxyribonucleotide (dNTP) starvation and cell cycle arrest. Collectively, terbinafine can inhibit CRC by reversing fungal dysbiosis, suppressing tumor cell proliferation, inhibiting fungus-induced MDSC infiltration, and restoring antitumor immune response.
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| 36. |
- Jakobsson, Johan, et al.
(author)
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Lentiviral Vectors for Use in the Central Nervous System.
- 2006
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 13:3, s. 484-493
-
Research review (peer-reviewed)abstract
- Lentiviral vectors have been used extensively as gene transfer tools for the central nervous system throughout the past decade since they transduce most cell types in the brain, resulting in high-level and long-term transgene expression. This review discusses some of the recent progress in this field, including preclinical gene therapy experiments in disease models, development of regulated vectors, and the application of siRNA's using lentiviral vectors. We also describe some of the features that make lentiviral vectors a likely candidate for human gene therapy in the brain.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Kanerva, Anna, et al.
(author)
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Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.
- 2015
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 23:2, s. 321-329
-
Journal article (peer-reviewed)abstract
- Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (From 170 to 208 days, P = 0.0012, N=148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N=90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N=37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.Molecular Therapy (2014); doi:10.1038/mt.2014.218.
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| 42. |
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| 43. |
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| 44. |
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Lehto, Taavi, et al.
(author)
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A Peptide-based Vector for Efficient Gene Transfer In Vitro and In Vivo
- 2011
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In: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 19:8, s. 1457-1467
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Journal article (peer-reviewed)abstract
- Finding suitable nonviral delivery vehicles for nucleic acid-based therapeutics is a landmark goal in gene therapy. Cell-penetrating peptides (CPPs) are one class of delivery vectors that has been exploited for this purpose. However, since CPPs use endocytosis to enter cells, a large fraction of peptides remain trapped in endosomes. We have previously reported that stearylation of amphipathic CPPs, such as transportan 10 (TP10), dramatically increases transfection of oligonucleotides in vitro partially by promoting endosomal escape. Therefore, we aimed to evaluate whether stearyl-TP10 could be used for the delivery of plasmids as well. Our results demonstrate that stearyl-TP10 forms stable nanoparticles with plasmids that efficiently enter different cell-types in a ubiquitous manner, including primary cells, resulting in significantly higher gene expression levels than when using stearyl-Arg9 or unmodified CPPs. In fact, the transfection efficacy of stearyl-TP10 almost reached the levels of Lipofectamine 2000 (LF2000), however, without any of the observed lipofection-associated toxicities. Most importantly, stearyl-TP10/plasmid nanoparticles are nonimmunogenic, mediate efficient gene delivery in vivo, when administrated intramuscularly (i.m.) or intradermally (i.d.) without any associated toxicity in mice.
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| 49. |
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| 50. |
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