Investigators at The Research Institute at Nationwide Children’s Hospital have identified a non-invasive method for delivering genes to the central nervous system, a strategy that penetrates the body’s protective blood-brain barrier with unprecedented success.
The blood-brain barrier (BBB) is a protective network of blood vessels and cells that prevents many substances from entering brain tissue and the central nervous system. While the BBB functions as a vital biological shield, it can also serve as a barrier to treating central nervous system disorders.
Previous gene therapy efforts to treat two of the most common motor neuron diseases, spinal muscular atrophy (SMA) and ALS (Lou Gehrig’s disease), have either failed to bypass the BBB, or are clinically irrelevant since they require interventions considered too numerous or too complicated.
In this study, which appears in Nature Biotechnology, members of the Center for Gene Therapy at The Research Institute used AAV9, a subtype of the adeno-associated virus, as the vehicle for gene transfer.
Using a single injection, researchers delivered AAV9 and examined its potential to transport genes to the central nervous system in neonatal and adult mouse models. Results showed AAV9 accessed the central nervous system with unmatched efficiency.
In the neonatal model, AAV9 preferentially targeted basic nerve cells (neurons). In adults it more often targeted astrocytes, the largest and most common nerve cells in the central nervous system. These differences suggest there is a developmental period during which viral access to these cell populations becomes restricted.
The precise mechanism by which AAV9 penetrates the BBB and facilitates gene transfer will require further study. Still, researchers believe the relatively non-invasive method described in this study could have important implications for gene therapy treatments in SMA and ALS. A suggested therapeutic for SMA is an increased expression of the survival motor neuron gene; this study’s single injection method could potentially achieve this outcome. Astrocytes, which were efficiently targeted in both the neonatal and adult models in this study, have been specifically linked to disease progression in ALS.
Additionally, new techniques stemming from this AAV9 research could target neurons in adults. Such strategies could provide new treatment options for diseases such as Huntington’s that involve multiple brain regions.