RNA Interference Screening Reveals Vaccine Target for Prevention of Autism Spectrum Phenotypes in a Drosophila melanogaster Autism-Associated Model

John T. Brugle, Ph.D and Mary Franz, Ph. D, M.P.H.

Wyoming Institute of Technology, Vaccine Development Division

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Abstract

Screening of an RNAi library in a Drosophila melanogaster autism-associated model identified a target that reduced autism associated phenotypes at the juvenile stage.  Bioinformatic approaches indicated that the RNAi construct interacted with a loci whose mammalian homolog has been implicated in the development of autism spectrum disorders through copy number variation.  Following identification of the target, an antigen based vaccine was developed.  Exposure of larval Drosophila melanogaster to the vaccine through maternal feed treatment resulted in reduced autism associated phenotypes.


 

Materials and Methods

RNAi lines targeting the known transcriptome of Drosophila melanogaster were developed and administered to adult populations through spiking of growth media.  D. melanogaster lines with autism associated dopamine receptor mutations were used to model autism spectrum disorders.  The progeny of the RNAi treated D. melanogaster were monitored from pupal to adult stage for autism associated phenotypes.  RNAi lines that reduced autism associated phenotypes were confirmed and their targets were identified using NCBI BLAST tools.  Using these targets, antigen based vaccines were developed and were confirmed to have curative effects when administered from the pupal to juvenile stage.

 

Results

Using an RNAi screening approach, a vaccine was developed that prevented the development of autism associated behaviors in a Drosophila melanogaster model.  Treatment with the developed vaccine caused a 94% reduction in autism associated behaviors across the tested population (n=1,293; p= 1×10-7).  The full list of RNAi lines tested is available in Supplement Table 1.   Complete analysis of phenotypes can be accessed in Supplemental Table 2.

 

Discussion

The identification of a novel vaccine for autism spectrum disorders using an RNAi reverse genetic approach confirms both the utility of Drosophila melanogaster as a model system for drug discovery and marks an exciting achievement in biomedical research.  The homology of this system to mammalian neurological systems enables this vaccine to be immediately deployed in clinical trials.

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