Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms

Neuropeptide Y Y1 receptor hippocampal overexpression via viral vectors is associated with modest anxiolytic-like and proconvulsant effects in mice.

Neuropeptide Y (NPY) exerts anxiolytic-and antidepressant-like effects in rodents that appear to be mediated via Y1 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY in the hippocampus or amygdala has previously been shown to confer anxiolytic-like effect in rodents. The present study explored an alternative and more specific approach: overexpression of Y1 receptors. Using a recombinant adeno-associated viral vector (rAAV) encoding the Y1 gene (rAAV-Y1), we, for the first time, induced overexpression of functional transgene Y1 receptors in the hippocampus of adult mice and tested the animals in anxiety- and depression-like behavior. Hippocampal Y1 receptors have been suggested to mediate seizure-promoting effect, so the effects of rAAV-induced Y1 receptor overexpression were also tested in kainate-induced seizures. Y1 receptor transgene overexpression was found to be associated with modest anxiolytic-like effect in the open field and elevated plus maze tests, but no effect was seen on depression-like behavior using the tail suspension and forced swim tests. However, the rAAV-Y1 vector modestly aggravated kainate-induced seizures. These data indicate that rAAV-induced overexpression of Y1 receptors in the hippocampus could confer anxiolytic-like effect accompanied by a moderate proconvulsant adverse effect. Further studies are clearly needed to determine whether Y1 gene therapy might have a future role in the treatment of anxiety disorders. (C) 2011 Wiley Periodicals, Inc

A neuroligin-1-derived peptide stimulates phosphorylation of the NMDA receptor NR1 subunit and rescues MK-801-induced decrease in long-term potentiation and memory impairment

Neuroligins (NLs) are postsynaptic adhesion molecules, interacting with presynaptic neurexins (NXs), which determine the differential formation of excitatory (glutamatergic, NL1) and inhibitory (GABAergic, NL2) synapses. We have previously demonstrated that treatment with a NL2-derived peptide, neurolide-2, reduces sociability and increase animal aggression. We hypothesized that interfering with NL1 function at the excitatory synapses might regulate synaptic plasticity and learning, and counteract memory deficits induced by N-methyl-d-aspartate (NMDA) receptor inhibition. First, neuronal NMDA receptor phosphorylation after treatment with NL1 or a mimetic peptide, neurolide-1, was quantified by immunoblotting. Subsequently, we investigated effects of neurolide-1 on long-term potentiation (LTP) induction in hippocampal slices compromised by NMDA receptor inhibitor MK-801. Finally, we investigated neurolide-1 effects on short- and long-term social and spatial memory in social recognition, Morris water-maze, and Y-maze tests. We found that subcutaneous neurolide-1 administration, restored hippocampal LTP compromised by NMDA receptor inhibitor MK-801. It counteracted MK-801-induced memory deficit in the water-maze and Y-maze tests after long-term treatment (24 h and 1–2 h before the test), but not after short-term exposure (1–2 h). Long-term exposure to neurolide-1 also facilitated social recognition memory. In addition, neurolide-1-induced phosphorylation of the NMDA receptor NR1 subunit on a site important for synaptic trafficking, potentially favoring synaptic receptor retention. Our findings emphasize the role of NL1–NMDA receptor interaction in cognition, and identify neurolide-1, as a valuable pharmacological tool to examine the in vivo role of postsynaptic NL1 in cognitive behavior in physiological and pathological conditions

Combined gene overexpression of neuropeptide Y and its receptor Y5 in the hippocampus suppresses seizures.

We recently demonstrated that recombinant adeno-associated viral vector-induced hippocampal overexpression of neuropeptide Y receptor, Y2, exerts a seizure-suppressant effect in kindling and kainate-induced models of epilepsy in rats. Interestingly, additional overexpression of neuropeptide Y in the hippocampus strengthened the seizure-suppressant effect of transgene Y2 receptors. Here we show for the first time that another neuropeptide Y receptor, Y5, can also be overexpressed in the hippocampus. However, unlike Y2 receptor overexpression, transgene Y5 receptors in the hippocampus had no effect on kainate-induced motor seizures in rats. However, combined overexpression of Y5 receptors and neuropeptide Y exerted prominent suppression of seizures. This seizure-suppressant effect of combination gene therapy with Y5 receptors and neuropeptide Y was significantly stronger as compared to neuropeptide Y overexpression alone. These results suggest that overexpression of Y5 receptors in combination with neuropeptide Y could be an alternative approach for more effective suppression of hippocampal seizures. (C) 2011 Elsevier Inc. All rights reserved