Adeno-Associated Viruses for Modeling Neurological Diseases in Animals: Achievements and Prospects

Abstract

Adeno-associated virus (AAV) vectors have become an attractive tool for efficient gene transfer into animal tissues. Extensively studied as the vehicles for therapeutic constructs in gene therapy, AAVs are also applied for creating animal models of human genetic disorders. Neurological disorders are challenging to model in laboratory animals by transgenesis or genome editing, at least partially due to the embryonic lethality and the timing of the disease onset. Therefore, gene transfer with AAV vectors provides a more flexible option for simulating genetic neurological disorders. Indeed, the design of the AAV expression construct allows the reproduction of various disease-causing mutations, and also drives neuron-specific expression. The natural and newly created AAV serotypes combined with various delivery routes enable differentially targeting neuronal cell types and brain areas in vivo. Moreover, the same viral vector can be used to reproduce the main features of the disorder in mice, rats, and large laboratory animals such as non-human primates. The current review demonstrates the general principles for the development and use of AAVs in modeling neurological diseases. The latest achievements in AAV-mediated modeling of the common (e.g., Alzheimer's disease, Parkinson's disease, ataxias, etc.) and ultra-rare disorders affecting the central nervous system are described. The use of AAVs to create multiple animal models of neurological disorders opens opportunities for studying their mechanisms, understanding the main pathological features, and testing therapeutic approaches.

Keywords: adeno-associated viruses; animal models of human disease; genetic neurological disorders; transgene delivery; viral vectors.

Figure 1

A general principle of creating recombinant AAV vectors. (A) Structure of the wild-type AAV. (B) System for rAAV production, and basic structure of the recombinant AAV vector.

Figure 2

Design of the AAV expression vectors for modeling neurological diseases. (A) AAV expression cassette suitable for the transfer of protein-coding transgenes. (B) Configuration of the AAV vector utilized for gene suppression via RNAi mechanism. P, promoter for RNA Pol II or III as indicated; CDS, the protein-coding DNA sequence; pA, poly(A) signal for Pol II-driven transcription termination; WPRE, woodchuck hepatitis virus posttranscriptional regulatory element; T, T-stretch for Pol III-driven transcription termination; shRNA, small hairpin RNA; miRNA, artificial microRNA.

Figure 3

Creating models of human neurological disorders by targeting the CNS of wild-type laboratory animals with AAV. The most critical steps include obtaining custom-designed neurotropic rAAV, virus administration into a laboratory animal at a selected dose and by the optimal route, and observing the phenotype after the disease onset. Neurotropic serotypes of AAV and routes of administration used by researchers to model neurological diseases in rodents and primates are exemplified. The doses of AAV used for CNS injections and systemic delivery are shown. GC/kg, genome copies per kilogram of the body weight.