Adeno-associated virus vector-mediated transduction in the cat brain

Area of Science:

• Neuroscience
• Gene Therapy
• Viral Vectors

Background:

• Adeno-associated virus (AAV) vectors enable therapeutic gene delivery for long-term protein production in the mouse brain.
• The significantly larger size of the human infant brain presents challenges for treating global neurometabolic disorders compared to mouse models.

Purpose of the Study:

• To evaluate the efficacy of three AAV serotypes (1, 2, and 5) in transducing cells within the cat brain, serving as a large mammalian model.
• To assess the potential of AAV vectors for gene therapy applications in larger brains relevant to human pediatric conditions.

Main Methods:

• Injected three AAV serotypes (AAV1, AAV2, AAV5) carrying the human beta-glucuronidase (GUSB) reporter gene into various brain regions of 8-week-old cats.
• Utilized in situ hybridization and enzyme histochemistry to evaluate gene expression and transduction efficiency 10 weeks post-injection.
• Employed heat stability differences between human and feline GUSB to distinguish reporter gene expression.

Main Results:

• AAV2 successfully transduced cells within the gray matter of the cat brain.
• AAV1 demonstrated broader transduction, affecting both gray and white matter, with greater efficiency in gray matter compared to AAV2.
• AAV5 did not yield detectable transduction in the feline brain under the study conditions.

Conclusions:

• AAV1 and AAV2 show promise for gene delivery in large mammalian brains, with AAV1 exhibiting superior transduction capabilities, particularly in white matter.
• These findings suggest AAV vectors, especially AAV1, could be viable for treating neurological disorders in larger brains, warranting further investigation.