Progress in gene therapy for neurological disorders

Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy

Gene therapy in epilepsy: neuropeptides and neurotrophic factors

Temporal lobe epilepsy (TLE) is the most common form of epilepsy among adult patients, and the most problematic one as seizures cannot be controlled by currently available drugs in 30 % of patients. Gene therapy based on overexpression of endogenous anti-epileptic agents such as the neuropeptide galanin and the glial cell line-derived neurotrophic factor (GDNF) represents a promising new approach for treatment of TLE. Using this strategy, supply of the respective therapeutic agent is restricted to the brain structure where seizure suppression is both necessary and sufficient, without disturbing normal function in other brain areas. In the present thesis, the anti-epileptic potential of local gene therapy-based increase of galanin and GDNF was determined in different animal models for TLE, i.e., kindling and status epilepticus. Target areas for localised overexpression were the hippocampus, a common structure of seizure origin, and the piriform cortex (PC), an area important in seizure generalisation. Galanin was overexpressed either in transgenic mice (paper I), or in rats using a viral vector (paper II). GDNF gene therapy was based on in vivo transduction of endogenous cells by viral vector (papers III and IV) or on transplantation of in vitro-manipulated, encapsulated cells (paper V). The data collected in this thesis show that increased supply of galanin and GDNF in the PC and/or the hippocampus influenced in particular generalised seizure activity in different models for TLE. These findings demonstrate that gene therapy based on overexpression of galanin and GDNF represents a promising approach for control of epileptic seizures. However, in order to also achieve modulation of initial seizure threshold and overall epileptogenesis, the pathways of galanin and GDNF anti-epileptic effects have to be understood in more detail and gene transfer methods have to be modified accordingly to reach optimal temporal and spatial overexpression and release

Can pyruvate and dihydroxyacetone (DHAP) improve athletic performance?

Pyruvate and dihydroxyacetone (DHAP) are marketed as nutritional supplements by health food stores and multilevel marketing distributors. Claims for pyruvate and dihydroxyacetone range from increasing endurance capacity, augmenting weight and fat loss, decreasing appetite, increasing metabolism, acting as an antioxidant, and lowering plasma lipids. Although several laboratory and clinical studies have investigated these claims, no studies to date have demonstrated the effectiveness of DHAP in improving athletic performance

Encapsulated galanin-producing cells attenuate focal epileptic seizures in the hippocampus

Encapsulated cell biodelivery (ECB) is a relatively safe approach, since the devices can be removed in the event of adverse effects. The main objectives of the present study were to evaluate whether ECB could be a viable alternative of cell therapy for epilepsy. We therefore developed a human cell line producing galanin, a neuropeptide that has been shown to exert inhibitory effects on seizures, most likely acting via decreasing glutamate release from excitatory synapses. To explore whether ECB of genetically modified galanin-producing human cell line could provide seizure-suppressant effects, and test possible translational prospect for clinical application, we implanted ECB devices bilaterally into the hippocampus of rats subjected to rapid kindling, a model for recurrent temporal lobe seizures

Activity-dependent volume transmission by transgene NPY attenuates glutamate release and LTP in subiculum

Neuropeptide Y (NPY) gene transduction of the brain using viral vectors in epileptogenic regions can effectively suppress seizures in animals, and is being considered as a promising alternative treatment strategy for epilepsy. Therefore, it is fundamental to understand the detailed mechanisms governing the release and action of transgene NPY in neuronal circuitries. Using whole-cell recordings from subicular neurons, we show that in animals transduced by recombinant adeno-associated viral (rAAV) vector carrying the NPY gene, transgene NPY is released during high-frequency activation of CA1-subicular synapses. Released transgene NPY attenuates excitatory synaptic transmission not only in activated, but also in neighboring, non-activated synapses. Such broad action of transgene NPY may prevent recruitment of excitatory synapses in epileptic activity and could play a key role in limiting the spread and generalization of seizures

VEGF receptor-2 (flk-1) overexpression in mice counteracts focal epileptic seizures.

Vascular endothelial growth factor (VEGF) was first described as an angiogenic agent, but has recently also been shown to exert various neurotrophic and neuroprotective effects in the nervous system. These effects of VEGF are mainly mediated by its receptor, VEGFR-2, which is also referred to as the fetal liver kinase receptor 1 (Flk-1). VEGF is up-regulated in neurons and glial cells after epileptic seizures and counteracts seizure-induced neurodegeneration. In vitro, VEGF administration suppresses ictal and interictal epileptiform activity caused by AP4 and 0 Mg(2+) via Flk-1 receptor. We therefore explored whether increased VEGF signaling through Flk-1 overexpression may regulate epileptogenesis and ictogenesis in vivo. To this extent, we used transgenic mice overexpressing Flk-1 postnatally in neurons. Intriguingly, Flk-1 overexpressing mice were characterized by an elevated threshold for seizure induction and a decreased duration of focal afterdischarges, indicating anti-ictal action. On the other hand, the kindling progression in these mice was similar to wild-type controls. No significant effects on blood vessels or glia cells, as assessed by Glut1 and GFAP immunohistochemistry, were detected. These results suggest that increased VEGF signaling via overexpression of Flk-1 receptors may directly affect seizure activity even without altering angiogenesis. Thus, Flk-1 could be considered as a novel target for developing future gene therapy strategies against ictal epileptic activity