Abstract
Several neurological and psychiatric disorders have been associated with impairments in GABAergic inhibitory neurons in the brain. Thus, in the current era of accelerated development of molecular medicine and biologically-based drugs, there is a need to identify gene regulatory sequences that can be utilized for selectively manipulating the expression of nucleic acids and proteins in GABAergic neurons. This is particularly important for the use of viral vectors in gene therapy. In this Mini Review, we discuss the use of various gene regulatory elements for targeting GABAergic neurons, with an emphasis on adeno-associated viral vectors, the most widely used class of viral vectors for treating brain diseases.
Highlights
The selected DNA sequence included a segment that was conserved between the mouse and human genes, extended 2,000 bases upstream of the mouse Sst start codon, and encompassed three conserved domains. This arrangement resulted in high gamma-aminobutyric acid (GABA) interneuron specificity and coverage in the hippocampus
PV is a small, Ca2+-binding protein that is prominently expressed in a subset of GABAergic neurons throughout the central nervous system (CNS)
The majority of studies reported to date were based on the analysis of fluorescent reporter proteins and did not assess therapeutic efficacy in disease models. We expect this state-ofthe-art to improve rapidly whereby GABA neuron-directed viral vectors will be tested in additional animal models of neurological and psychiatric disorders, with the expectation that some of these candidate gene regulatory elements in combination with therapeutic transgenes will advance to clinical testing
Summary
The distal-less homeodomain transcription factor (DLX) family is a gene family highly conserved across vertebrates. The DLX genes are grouped into bicistronic gene clusters and are regulated by intergenic enhancer sequences with high degrees of homology between mice and humans. Analogous enhancer sequences are found in human DLX genes: h12R (found in DLX1/2) and h56D (found in DLX5/6) [14]. Each of these enhancers, when packaged with a minimal promoter onto rAAV vectors, effectively direct transgene expression to GABAergic neurons. All of the aforementioned DLX enhancers (I12b, I56i, h12R, and h56D) directed transgene expression to murine cortical and hippocampal GABAergic neurons with approximately 90% or greater specificity [(10–12, 14); see Table 1].
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