AAV-mediated gene delivery in Dp71-null mouse model with compromised barriers

Area of Science:

• Ophthalmology
• Neuroscience
• Cell Biology

Background:

• The blood-retinal barrier (BRB) is crucial for vision; its breakdown contributes to retinal diseases like diabetic retinopathy.
• Dystrophin Dp71, a Müller cell protein, is vital for BRB integrity, affecting AQP4 and Kir4.1 channel function.
• Dp71-null mice exhibit BRB permeability, serving as a model for studying retinal barrier dysfunction.

Purpose of the Study:

• To investigate Müller cell involvement in the BRB and inner limiting membrane of Dp71-null mice.
• To compare Müller cell transduction patterns in Dp71-null and wild-type mice using an Adeno-associated virus (AAV) vector.
• To understand barrier function in a model of permeable BRB and its implications for gene therapy.

Main Methods:

• Intravitreal injection of ShH10-GFP, an Adeno-associated virus (AAV) variant targeting Müller cells.
• Comparative analysis of Müller cell transduction in Dp71-null and wild-type mice.
• Assessment of inner limiting membrane permeability and viral cell-surface receptor expression.

Main Results:

• Müller cell transduction patterns significantly differ between Dp71-null and wild-type mice.
• Dp71 deficiency alters viral cell-surface receptor expression and inner limiting membrane permeability.
• Intravitreal AAV injection in Dp71-null mice did not result in systemic virus leakage, despite BRB compromise.

Conclusions:

• Müller cells exhibit altered characteristics in Dp71-null mice, affecting BRB and inner limiting membrane integrity.
• Dp71 deficiency impacts viral tropism and barrier function, relevant for AAV-mediated gene therapy strategies.
• The Dp71-null mouse model provides insights into BRB pathophysiology and potential therapeutic interventions.