Several AAV capsids have been engineered or identified for their ability to cross the blood-brain barrier (BBB), enabling efficient gene delivery to the central nervous system (CNS). Below is a list of notable AAV capsids with demonstrated BBB-crossing capabilities:

• Naturally Occurring AAV Capsids with BBB Penetration
  • AAV9: One of the most well-studied capsids for CNS targeting. Efficiently crosses the BBB in neonatal and adult models, making it a popular choice for treating neurological disorders like spinal muscular atrophy (SMA).
  • AAVrh.10: A rhadinovirus-derived AAV variant with strong CNS tropism. Demonstrates robust BBB penetration and widespread transduction in the brain.
• Engineered AAV Capsids with Enhanced BBB Penetration
  • AAV-PHP.B: was developed through directed evolution in mice, a process that involves creating a library of capsid variants and selecting those with the desired properties. It is derived from AAV9, a naturally occurring serotype known for its ability to cross the BBB, particularly in neonatal models. The capsid contains specific mutations, such as the insertion of a 7-amino acid peptide, which significantly enhances its ability to interact with the BBB and enter the CNS.
  • AAV-PHP.eB: AAV-PHP.eB was developed through additional rounds of directed evolution from the AAV-PHP.B capsid. The capsid contains further mutations that enhance its ability to transduce CNS tissues more efficiently than AAV-PHP.B.
  • AAV-PHP.C2 was also able to successfully transduce the BALB/cJ brain and spinal cord.
  • AAV.CAP-B10 and AAV.CAP-B22: building upon the foundation of AAV-PHP.eB and incorporating specific modifications at the VR-IV (Variable Region IV) site.
  • AAV-BR1 is an AAV2 capsid variant showing enhanced transduction of brain microvascular endothelial cells in mice following intravenous injection. Kawabata et al. discovered that one amino acid substitution in the BR1 capsid (designated BR1N) makes the capsid highly permeable to the blood-brain barrier.

  • AAV-F mediates 65-fold higher transgene expression in astrocytes and 171-fold higher expression in neurons compared to AAV9. Demonstrates widespread and robust gene expression in the brain cortex, making it ideal for studying and treating cortical-related disorders. High transduction efficiency is consistent across both male and female mice, ensuring reliable performance in preclinical studies. Sustained efficiency in two commonly used mouse strains, C57BL/6 and BALB/c, enhancing its utility for diverse research applications.

  • AAV9P31: outperformed the parental AAV9 and AAV-PHP.eB, showing strong and homogeneous transduction of mouse brain following intravenous (i.v.) administration. The modification incorporated in this capsid consists of an insertion of the heptapeptide WPTSYDA between residues 588 and 589 of the hypervariable surface loop VIII. A recent study has identified carbonic anhydrase IV (CA-IV) as the receptor mediating BBB transcytosis of AAV9P31. However, a comparable performance of AAV9P31 to bypass the BBB in rats and macaques was not observed.

  • AAV-MaCPNS1/2 are engineered AAV capsids based on AAV9, designed to efficiently transduce both the peripheral nervous system (PNS) and central nervous system (CNS) across multiple species. These capsids have been tested in rodents (mice and rats) and non-human primates (NHPs, including marmosets and rhesus macaques). When administered intravenously, both AAV-MaCPNS1 and AAV-MaCPNS2 demonstrate robust transduction of the PNS in rodents and effective targeting of both the PNS and CNS in NHPs. This makes them highly versatile tools for preclinical studies and potential therapeutic applications in neurological disorders.
  • AAV-PHP.S: A capsid optimized for peripheral nervous system (PNS) and CNS targeting in mice. Demonstrates efficient BBB crossing in rodent models.
  • AAV-X1 and AAV-X1.1 were developed by combining directed evolution (to generate diverse capsid libraries) and semi-rational engineering (to introduce specific modifications based on structural insights).. They target brain endothelial cells specifically and efficiently following systemic delivery in mice with a ubiquitous promoter. These novel AAVs across rodent models (genetically diverse mouse strains and rats), non-human primates (marmosets and rhesus macaques), and ex vivo human brain slices, demonstrating brain endothelial-specific cell targeting in rodents and broad CNS targeting in primates. 
  • AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques with improved efficiency in the brain of multiple NHP species: marmoset, rhesus macaque, and green monkey. CAP-Mac is neuron-biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques, and is vasculature-biased in adult marmosets. 
  •  AAV-MDV1A significantly outperformed AAV9 in both transgene delivery and expression in the brain of all groups of mice, demonstrating between 25- and 160-fold improvement in transgene expression in the brain of female C57BL/6J and male BALB/cJ mice.
  • AAV9P801 is an engineered AAV capsid developed using the AAV9 VR-VIII random peptide insertion library. This capsid has emerged as a leading candidate for BBB crossing and CNS transduction following intravenous administration in Cynomolgus Macaques. 
  • VCAP-102, a TRACER-engineered rAAV9 variant, displayed 20–90-fold increased transduction in diverse brain regions of NHPs compared to rAAV9. Iterative evolution of VCAP-102 led to capsid variants with 6–7-fold further improved BBB penetration. 
  • VCAP-100: TRACER-developed VCAP-100 derivatives showed up to 300-fold liver detargeting and six-fold higher brain transduction in NHPs over its parental AAV5.