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Retinal Development and Disorders / Virus-based Gene Therapy Research / CRISPR and Genetic Engineering · Journal article
Fluids and Barriers of the Cns · July 31, 2026
Early or partial results. Treat as a signal, not a conclusion.
This preclinical study reports successful tropism of a novel AAV6-derived capsid (ShH10 Y445F) for choroid plexus epithelium in rodent and porcine models, with functional demonstration of CRISPR/Cas9-mediated aquaporin-1 knockdown. Transduction distribution is uneven and lateralized, which the authors identify as a significant barrier to clinical translation where complete choroid plexus coverage may be necessary.
Preclinical proof-of-concept study combining in vitro tissue explant culture and in vivo rodent stereotactic injection. Mouse, rat, and porcine tissue explant cultures; mouse brain (in vivo). Intervention: Stereotactic intracerebroventricular injection of AAV6-derived capsid ShH10 Y445F carrying either GFP transgene or CRISPR/Cas9 system targeting aquaporin-1.
ShH10 Y445F demonstrates choroid plexus epithelium tropism in mouse, rat, and porcine tissue explant cultures In vivo tropism confirmed in mouse following stereotactic intracerebroventricular injection CRISPR/Cas9 system successfully delivered via AAV reduces target protein (aquaporin-1) expression in transduced choroid plexus epithelial cells
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This work establishes a new capsid variant with choroid plexus tropism and demonstrates functional gene silencing capability, but uneven distribution following unilateral injection represents a material challenge for clinical development. Strategies to achieve complete choroid plexus coverage would likely be required before clinical efficacy studies.
Early-stage preclinical work demonstrating proof-of-concept for a novel AAV capsid in tissue culture and small animal models, with identified technical barriers to clinical translation.
As stated by the source record.
This work establishes a new capsid variant with choroid plexus tropism and demonstrates functional gene silencing capability, but uneven distribution following unilateral injection represents a material challenge for clinical development. Strategies to achieve complete choroid plexus coverage would likely be required before clinical efficacy studies.
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What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Abstract Using adeno-associated virus to transfer genetic information to the choroid plexus has emerged as a promising route for long-term gene therapy in the brain for a variety of conditions. Overexpression of proteins has proved effective in small animal models but few attempts have been made to translate this technology to clinic, suppress the activity of a protein of interest, or further expand the limited capsid serotypes known to have choroid plexus tropism. We utilise transfer of green fluorescent protein to show choroid plexus epithelium tropism for novel AAV6 derived capsid ShH10 Y445F in mouse, rat and porcine tissue explant cultures. In vivo tropism is shown in the mouse following stereotactic intracerebroventricular injection. We examined the distribution of viral transduction across the choroid plexus in all four ventricles following a single unilateral intracerebroventricular injection using both green fluorescent protein as a transgene, but also the CRISPR/Cas9 system to deliver permanent knockdown of apical water channel aquaporin-1. Quantitative immunofluorescence and SURVEYOR assay were used to statistically assess the magnitude and extent of choroid plexus knockdown across the ventricular system. We conclude that serotype ShH10 Y445F targets choroid plexus epithelium in mouse, rat and pig; and when carrying the CRISPR/Cas9 system can reduce target protein expression in these cells. Transduced choroid plexus epithelial cells distribute unevenly with a bias toward the lateral ventricle on the injected side and a preferential infection of choroid plexus in the lateral over the third and fourth ventricles. Overcoming irregular distribution represents a challenge for clinical translation of this technology where clinical efficacy may require manipulation of the entire choroid plexus.
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