Lentiviruses have the capacity to enter and integrate their genetic material into cells that are not dividing. This property is retained in vectors based on these agents. They can thus effect gene delivery to cells that are difficult to transduce such as cardiac myocytes in vitro and in vivo. They are also relatively efficient at entering dividing cells and can transduce stem cells and vascular endothelium. They have a substantial gene-carrying capacity of up to around 9 kb. They do not trigger an inflammatory response and are thus useful when proinflammatory agents are undesirable, such as in transplantation. Their ease of cloning and well-understood molecular biology have made them highly suitable for gene delivery to the heart.
"The more recent two or three plasmid systems have increased the safety profile of lentiviral-based vectors but concerns remain regarding the possibility of recombination events producing a replication competent virus . However, the capacity of these vectors, of approximately 9 kb, makes them a very attractive option for future gene therapy research . "
[Show abstract][Hide abstract] ABSTRACT: Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.
"Further specificity can be given through the use of the human glial fibrillary acidic promoter (hGFAP) or neuron-specific enolase promoter (rNSE), giving glial or neuronal specificities respectively (Jakobsson 2006). This class of vectors certain several advantages, including a relatively large capacity for cloned genes (approximately nine kilobases) (Zhao 2007), but concerns relate to the possibility of recombination events, producing replication-competent virus. The use of two or three plasmid based transfection systems, in which the capsid assembly genes are genetically isolated has increased the safety profile of this class of vectors (Zufferey 1997) and this class looks particularly promising for future studies. "
[Show abstract][Hide abstract] ABSTRACT: Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile.
Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies.
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