Modified AAV5 Capsid for Enhanced Organ-Specific Gene Therapy Delivery

Background & Unmet Need

• The biodistribution of adeno-associated virus (AAV) vectors is dependent on the structure of the AAV capsid, route of administration, and specificity of AAV receptors for the cell populations of different organs
• Intravenous (IV) administration of naturally occurring adeno-associated virus (AAV) vectors are liver tropic, with 40–60% of the vector reaching the liver
• AAV capsids that are directed towards other organs (such as lung) would be useful for therapy of non-liver-based diseases
• Unmet Need: Novel gene therapy delivery methods to improve organ-specific uptake

Technology Overview

• The Technology: Recombinant AAV vector with altered tropism for enhanced targeting of specific organs
• The Discovery: Adding positively charged lysine residues to the AAV capsid enhances the ability of the virus to adhere to negatively charged glycans, commonly distributed on lung capillary endothelium
• PoC Data: AAV5-PK2-hAAT (containing two lysine residues after amino acid position 575 in the capsid protein) provided 2.5x log higher lung-to-liver ratio compared to a standard AAV5 vector
• AAV5-PK2-hAAT had 79x less vector genomes in the liver, 21x less vector in the spleen, and 52x less in the ileum
• Vector distribution of AAV5-PK2-hAAT was similar in the heart, brain, and kidney
• hAAT mRNA liver distribution was significantly lower for the AAV5-PK2 (197x less) with modestly increased hAAT mRNA in the lung (1.3x more)

Technology Applications

• Method for targeting AAV vectors to specific organs based on the administration route
• “Sticky” capsid modification strategy should be applicable for all AAV vectors

Technology Advantages

• Minimal modifications to the vector are required to enhance organ-specific delivery
• Reduces off-target “spill” of the vector to the systemic circulation and other organs