| 1. |
|
|
| 2. |
|
|
| 3. |
- Avaliani, N., et al.
(författare)
-
DREADDs suppress seizure-like activity in a mouse model of pharmacoresistant epileptic brain tissue
- 2016
-
Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 23:10, s. 760-766
-
Tidskriftsartikel (refereegranskat)abstract
- Epilepsy is a neurological disorder with a prevalence of ≈1% of general population. Available antiepileptic drugs (AEDs) have multiple side effects and are ineffective in 30% of patients. Therefore, development of effective treatment strategies is highly needed, requiring drug-screening models that are relevant and reliable. We investigated novel chemogenetic approach, using DREADDs (designer receptors exclusively activated by designer drugs) as possible inhibitor of epileptiform activity in organotypic hippocampal slice cultures (OHSCs). The OHSCs are characterized by increased overall excitability and closely resemble features of human epileptic tissue. Studies suggest that chemically induced epileptiform activity in rat OHSCs is pharmacoresistant to most of AEDs. However, high-frequency electric stimulus train-induced bursting (STIB) in OHSCs is responsive to carbamazepine and phenytoin. We investigated whether inhibitory DREADD, hM4Di, would be effective in suppressing STIB in OHSC. hM4Di is a mutated muscarinic receptor selectively activated by otherwise inert clozapine-N-oxide, which leads to hyperpolarization in neurons. We demonstrated that this hyperpolarization effectively suppresses STIB in mouse OHSCs. As we also found that STIB in mouse OHSCs is resistant to common AED, valproic acid, collectively our findings suggest that DREADD-based strategy may be effective in suppressing epileptiform activity in a pharamcoresitant epileptic brain tissue.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Danielsson, Angelika, 1981-, et al.
(författare)
-
An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood
- 2010
-
Ingår i: Gene Therapy. - : Nature Publishing Group. - 0969-7128 .- 1476-5462. ; 17:6, s. 752-762
-
Tidskriftsartikel (refereegranskat)abstract
- Polyethylene glycol coating (PEGylation) of adenovirus serotype 5 (Ad5) has been shown to effectively reduce immunogenicity and increase circulation time of intravenously administered virus in mouse models. Herein, we monitored clot formation, complement activation, cytokine release and blood cell association upon addition of uncoated or PEGylated Ad5 to human whole blood. We used a novel blood loop model where human blood from healthy donors was mixed with virus and incubated in heparin-coated PVC tubing while rotating at 37°C for up to 8 hours. Production of the complement components C3a and C5a and the cytokines IL-8, RANTES and MCP-1 was significantly lower with 20K-PEGylated Ad5 than with uncoated Ad5. PEGylation prevented clotting and reduced Ad5 binding to blood cells in blood with low ability to neutralize Ad5. The effect was particularly pronounced in monocytes, granulocytes, B-cells and T-cells, but could also be observed in erythrocytes and platelets. In conclusion, PEGylation of Ad5 can reduce the immune response mounted in human blood, although the protective effects are rather modest in contrast to published mouse data. Our findings underline the importance of developing reliable models and we propose the use of human whole blood models in pre-clinical screening of gene therapy vectors.
|
|
| 10. |
- de Muinck, Ebo D., et al.
(författare)
-
Progress and prospects: Cell based regenerative therapy for cardiovascular disease
- 2006
-
Ingår i: Gene Therapy. - : Nature Publishing Group. - 0969-7128 .- 1476-5462. ; 13:8, s. 659-671
-
Forskningsöversikt (refereegranskat)abstract
- Experimental and clinical studies are progressing simultaneously to investigate the mechanisms and efficacy of progenitor cell treatment after an acute myocardial infarction and in chronic congestive heart failure. Multipotent progenitor cells appear to be capable of improving cardiac perfusion and/or function; however, the mechanisms still are unclear, and the issue of whether or not trans-differentiation occurs remains unsettled. Both experimentally and clinically, cells originating from different tissues have been shown capable of restoring cardiac function, but more recently multiple groups have identified resident cardiac progenitor cells that seem to participate in regenerating the heart after injury. Clinically, cells originating from blood or bone marrow have been proven to be safe whereas injection of skeletal myoblasts has been associated with the occurrence of ventricular arrhythmias. Myoblasts can transform into rapidly beating myotubes; however, thus far convincing evidence for electro-mechanical coupling between myoblasts and cardiomyocytes is lacking. Moving forward, mechanistic studies will benefit from the use of genetic markers and Cre/lox reporter systems that are less prone to misinterpretation than fluorescent antibodies, and a more convincing answer regarding therapeutic efficacy will come from adequately powered randomized placebo controlled trials.
|
|
