Vectors based on lentiviruses are opening up new approaches for the treatment of neurodegenerative diseases. Currently, the equine infectious anaemia virus (EIAV) vector is one of the most attractive gene delivery systems with respect to neuronal tropism. The aim was to validate EIAV-lentiviral vectors as a gene delivery system for neurotrophic factor genes in an animal model of Parkinson's disease. EIAV carrying the glial cell line-derived neurotrophic factor (GDNF) gene was unilaterally injected into rat striatum and above the substantia nigra (SN). One week later, the rats received a 6-OHDA lesion into the ipsilateral striatum. GDNF delivery led to extensive expression of GDNF protein within the striatum. In addition, near complete protection against dopaminergic cell death was observed in the GDNF-treated group.
Almost 90 years ago, Canavan Disease (CD) was described for the first time. Since then, the scientific community has unsuccessfully sought to cure this devastating leukodystrophy and understand its pathomechanism. Early hope for gene therapy was fueled with the cloning of the disease causing gene, Aspartoacylase, in 1993. Unfortunately, the only clinical trial for CD gene therapy failed to show significant clinical improvements in Canavan patients. At that time, animal models for CD were just engineered and comprehensive pre-clinical evaluation of CD gene therapy was missing. Earlier, we reported that our 1 st generation IV delivered pre-clinical gene therapy was able to rescue early lethality and partially restored motor function in a mouse model of CD. Now in its 3 rd generation, our gene therapy cures the disease in Canavan mice by a single intravenous injection, shown by behavioral, cognitive, and neuropathology tests. Taking advantage of this complete reversal of the disease, we used whole brain neurometabolome profiling to closely monitor the molecular efficacy and mechanism(s) in curing Canavan disease in mouse. Hierarchical cluster analysis (HCA) shows complete restoration of the disease associated metabolic derangements, including the array of detected myelin lipids. In the next step, we hypothesized that the metabolic nature of Canavan Disease mandates the origin of its pathomechanism in the metabolic regulation. We identified a specific dysregulation in the energy metabolism in vitro and in vivo that suggests the self-digestion of myelin for energetic purposes, calling current hypotheses about the Canavan disease pathomechanism into question. Currently, we are intensifying our insight into this mechanism by mircoRNAome, transcriptome analyses, a series of in vitro cell culture models, as well as supplementary and alternative strategies for the treatment of Canavan Disease. In summary, our data demonstrates strong evidence that rAAV mediated pre-clinical gene therapy not only cures the Canavan phenotype but also corrects the extensive neurometabolome, which provides meticulous evidence for gene therapy's high efficacy. Furthermore, we revealed a new pathomechanism that supports a paradigm shift in our perception of the function of ASPA and NAA in Canavan disease and their potential implications in other CNS and metabolic disorders in general.
Niemann-Pick disease, type C1 disease (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. NPC1 commonly manifests in childhood, and there are no approved treatments to delay, stop, or reverse the fatal neurodegeneration that is the hallmark of this disorder. New therapies for patients with NPC1 need to be developed. Defects in the NPC1 gene are the cause of this disease. A murine model of NPC1, Npc nih (also called BALB/(cNctr-Npc1 m1N /J), arising from a spontaneous frame-shift mutation in the Npc1 gene has been described. Npc nih homozygotes (Npc1 -/-) have an early, severe, and rapidly progressing disease, which is characterized by weight loss, ataxia, and lethality by 9 weeks of age. To test the potential efficacy of gene therapy with the goal of developing a new treatment for NPC patients, we constructed an adeno-associated virus (AAV) serotype 9 to deliver the human NPC1 gene under the transcriptional control of the neuronal-specific promoter, mouse calcium/calmodulin-dependent protein kinase II (CaMKII). Npc1 -/mice received 1x10 12 GC of AAV9-CaMKII-NPC1 or an equivalent reporter control, AAV9-CaMKII-GFP, between 20 and 25 days of life delivered by retro-orbital injection. To achieve neuronal transduction, we relied upon the well-established property of AAV9 vectors to cross the blood-brain barrier and transduce neurons after systemic delivery. Relative to the untreated or AAV-GFP treated Npc1 -/mice (n=15, mean survival 66 days, SD=0.89), the Npc1 -/mice that received AAV9-CaMKII-NPC1 exhibited an increased life span (n=9, mean survival 105 days, SD=30; P<0.02) Although the AAV9-CaMKII-NPC1 treated Npc1 -/mice did not achieve a normal life expectancy or the same weight of wild-type mice, our results demonstrate, for the first time, the potential efficacy of systemic AAV gene therapy as a therapeutic option in patients with NPC1.
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