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Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington's Disease. | LitMetric

AI Article Synopsis

  • * Traditional delivery methods for gene therapy face challenges due to the blood-brain barrier, but focused ultrasound (FUS) offers a non-invasive alternative to enhance gene delivery.
  • * In studies with AAV9 vectors in both wild-type and HD mouse models, FUS successfully improved delivery efficacy, although there were concerns regarding decreased gene expression in older HD mice without increasing astrocytosis.

Article Abstract

Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the gene. There are no cures for HD, but the genetic basis of this disorder makes gene therapy a viable approach. Adeno-associated virus (AAV)-miRNA-based therapies have been demonstrated to be effective in lowering HTT mRNA; however, the blood-brain barrier (BBB) poses a significant challenge for gene delivery to the brain. Delivery strategies include direct injections into the central nervous system, which are invasive and can result in poor diffusion of viral particles through the brain parenchyma. Focused ultrasound (FUS) is an alternative approach that can be used to non-invasively deliver AAVs by temporarily disrupting the BBB. Here, we investigate FUS-mediated delivery of a single-stranded AAV9 bearing a cDNA for GFP in 2-month-old wild-type mice and the zQ175 HD mouse model at 2-, 6-, and 12-months. FUS treatment improved AAV9 delivery for all mouse groups. The delivery efficacy was similar for all WT and HD groups, with the exception of the zQ175 12-month cohort, where we observed decreased GFP expression. Astrocytosis did not increase after FUS treatment, even within the zQ175 12-month group exhibiting higher baseline levels of GFAP expression. These findings demonstrate that FUS can be used to non-invasively deliver an AAV9-based gene therapy to targeted brain regions in a mouse model of Huntington's disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11206648PMC
http://dx.doi.org/10.3390/pharmaceutics16060710DOI Listing

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