PhP.B Enhanced Adeno-Associated Virus Mediated-Expression Following Systemic Delivery or Direct Brain Administration

Area of Science:

• Neuroscience
• Gene Therapy
• Virology

Background:

• Adeno-associated viruses (AAVs) are crucial for gene therapy.
• AAV9 can cross the blood-brain barrier (BBB) noninvasively.
• AAV5 is effective for neurodegenerative diseases but requires invasive delivery.

Purpose of the Study:

• To compare the efficacy of AAV9-PhP.B and AAV5-PhP.B for central nervous system gene delivery.
• To evaluate noninvasive versus invasive delivery methods for these AAV vectors.
• To assess the potential of modified AAVs for therapeutic miRNA delivery.

Main Methods:

• Engineered AAV9 and AAV5 vectors with the PhP.B peptide using an insect cell-based system.
• Administered vectors intravenously (IV) and intrastriatally (IStr) in mice.
• Quantified vector DNA and therapeutic miRNA expression in brain regions.

Main Results:

• AAV9-PhP.B demonstrated similar transduction in the striatum and cortex regardless of IV or IStr delivery.
• Intrastriatal AAV5 delivery resulted in significantly higher vector DNA and miRNA in target regions compared to IV AAV9-PhP.B.
• PhP.B addition to AAV5 enhanced liver transduction but did not improve BBB crossing.

Conclusions:

• Achieving high local gene expression noninvasively remains a challenge.
• Intraparenchymal AAV5 delivery is preferred for localized therapeutic miRNA delivery.
• Humanized AAV9-PhP.B shows promise for widespread brain and peripheral transduction.