ABSTRACT
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene-environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition.
Subject(s)
Autism Spectrum Disorder/complications , Autism Spectrum Disorder/metabolism , Behavioral Symptoms/etiology , Glycemic Index , Animals , Autism Spectrum Disorder/genetics , C-Reactive Protein/metabolism , Calcium-Binding Proteins/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Disease Models, Animal , Doublecortin Domain Proteins , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Gliosis/etiology , Grooming/physiology , Homer Scaffolding Proteins , Humans , Inositol 1,4,5-Trisphosphate Receptors/genetics , Interpersonal Relations , Maze Learning/classification , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Microtubule-Associated Proteins/metabolism , Mutation/genetics , Nerve Tissue Proteins/metabolism , Neuropeptides/metabolism , Oxidoreductases/metabolism , ras GTPase-Activating Proteins/metabolismABSTRACT
Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.
