Comparative Transduction Profiling of Four Intravenously Delivered AAV Capsids in the Neonatal Murine Nervous System

Area of Science:

• Neuroscience
• Gene Therapy
• Viral Vector Engineering

Background:

• Adeno-associated virus (AAV) capsid selection is crucial for effective gene therapy targeting the nervous system.
• Systemic delivery of AAV9, rAAV2-retro, AAV-PHP.eB, and AAV-MacpnS1 shows CNS transduction potential.
• Comparative analysis of these AAV capsids in a neonatal model is lacking.

Purpose of the Study:

• To systematically compare the tropism, efficiency, and safety of four AAV capsids (AAV9, rAAV2-retro, AAV-PHP.eB, AAV-MacpnS1) after intravenous administration in neonatal mice.
• To evaluate transgene expression across CNS regions and peripheral organs (heart, liver).
• To assess biochemical indicators of hepatic stress associated with each capsid.

Main Methods:

• Intravenous administration of four distinct AAV capsids into neonatal C57BL/6 mice.
• Quantitative assessment of transgene expression in various CNS regions, heart, and liver.
• Evaluation of biochemical markers for hepatic stress.

Main Results:

• Distinct and capsid-specific transduction profiles were observed.
• AAV9 and AAV-MacpnS1 demonstrated widespread CNS and peripheral organ transduction; AAV-MacpnS1 showed superior thalamic neuronal tropism but higher hepatic stress.
• rAAV2-retro exhibited high specificity for medulla and spinal motor neurons with a favorable safety profile; AAV-PHP.eB showed broad spinal cord transduction but low specificity for cholinergic motor neurons.
• AAV9 and AAV-MacpnS1 efficiently transduced DRG neurons, unlike rAAV2-retro and AAV-PHP.eB.

Conclusions:

• The study provides a comparative framework for AAV capsid selection in gene therapy.
• Findings guide the choice of AAV vectors for neuroscience research and targeted gene therapies, especially for neurodevelopmental and motor neuron disorders.
• Intravenous delivery in neonates is a viable strategy for specific AAV capsid applications.