AAV Gene Therapy Drug Development and Translation of Engineered Ocular and Neurotropic Capsids: A Systematic Review...

Area of Science:

• Biotechnology and Gene Therapy
• Neuroscience
• Ophthalmology

Background:

• Naturally occurring adeno-associated virus (AAV) serotypes often exhibit limited tissue specificity and efficiency.
• This necessitates the engineering of novel AAV capsids to improve targeting for therapeutic applications.
• Significant research efforts have focused on developing enhanced AAV capsids over recent years.

Purpose of the Study:

• To systematically review and identify engineered neurotropic and ocular AAV capsids tested in non-human primates.
• To illustrate advances in capsid engineering for enhanced specificity and efficiency in gene therapy.
• To highlight the utility of Natural Language Processing (NLP) in analyzing AAV capsid literature.

Main Methods:

• Utilized Linguamatics i2E NLP tool to query PubMed abstracts for AAVs, administration routes, and target organs/species.
• Developed an optimized search strategy to refine 5907 initial hits to 36 relevant abstracts.
• Categorized identified novel capsids based on administration route: systemic, direct CNS injection, and ocular.

Main Results:

• Identified numerous novel engineered AAV capsids with enhanced neurotropic and ocular tropism.
• Notable examples include AAV-PHP.eB for systemic CNS targeting, AAV2.Retro for direct CNS injection, and AAV.44.9 (E531D) for ocular administration.
• Engineered capsids demonstrated improved tissue specificity, pharmacokinetics, pharmacodynamics, and reduced off-target effects compared to parent serotypes.

Conclusions:

• Engineered AAV capsids represent a significant advancement for targeted gene therapies in the central nervous system and eye.
• These novel capsids offer improved translational potential and drug development considerations.
• NLP and Large Language Models are effective tools for summarizing and characterizing the rapidly evolving field of engineered AAV capsids.