Targeting the peripheral nervous system in adipose tissue with engineered AAV vectors

Area of Science:

• Neuroscience
• Metabolic Research
• Gene Therapy

Background:

• Adipose tissue innervation is crucial for energy balance and metabolic regulation.
• Targeted gene delivery to peripheral nerves in adipose tissue presents significant challenges.
• Understanding adipose nerve function requires effective tools for nerve fiber transduction.

Purpose of the Study:

• To systematically evaluate adeno-associated virus (AAV) capsids for targeted gene delivery to adipose tissue nerves.
• To optimize AAV delivery methods for selective transduction of peripheral nerves within adipose tissue.
• To enable mechanistic studies and therapeutic development for metabolic and neuropathic disorders.

Main Methods:

• Comparative analysis of seven AAV serotypes (AAV1, AAVrg, AAV5, AAV9, AAV-PHP.S, AAV-MaCPNS1, AAV-MaCPNS2) in C57BL/6J mice.
• Optimization of intra-adipose delivery through titration studies to enhance specificity and minimize off-target effects.
• Utilized Cre-dependent AAVs for selective targeting of Nav1.8+ sensory nerves and employed Tetbow for multicolor axon labeling and chemogenetic effector delivery.

Main Results:

• AAV-PHP.S was identified as the most efficient serotype for transducing nerve fibers in inguinal subcutaneous white adipose tissue (ing-scWAT).
• Optimized intra-adipose delivery protocols successfully minimized off-target expression and achieved selective nerve targeting.
• Demonstrated successful selective targeting of Nav1.8+ sensory nerves, enabling advanced visualization and functional manipulation.

Conclusions:

• Established effective conditions for AAV-mediated transgene delivery to adipose tissue nerves.
• AAV-PHP.S provides a promising tool for investigating adipose tissue innervation and its role in metabolic functions.
• This approach opens new avenues for studying neuropathic disorders and developing targeted therapies.