Adeno-associated virus (AAV) vectors are the leading delivery platform for gene therapy targeting neurodegenerative diseases. These non-pathogenic viruses have become the vector of choice for CNS gene delivery due to their favorable safety profile, long-term expression, and ability to transduce both dividing and non-dividing cells.
- Small, non-enveloped viruses (~25 nm diameter)
- Single-stranded DNA genome (~4.7 kb)
- Composed of icosahedral capsid protein shell
- Requires helper virus for replication
Over 100 naturally occurring AAV serotypes have been identified, each with distinct tissue tropisms:
- AAV1, AAV2, AAV5, AAV9: Neuronal transduction
- AAV9: Most commonly used for CNS delivery; crosses BBB in some contexts
- AAV-PHP.B/PHP.eB: Engineered variants with enhanced CNS transduction
- AAV2: Traditional choice; binds to heparan sulfate receptors
- Maximum cargo: ~4.7 kb single-stranded DNA
- Limited for large gene delivery (e.g., full GBA1, large regulatory regions)
- Solutions: Split-intein systems, dual-vector approaches, minimal promoters
- Cell surface binding: AAV capsid binds to specific receptors (e.g., AAV9 binds to galactose)
- Internalization: Receptor-mediated endocytosis
- Endosomal escape: Capsid undergoes conformational changes
- Nuclear entry: Virions traffic to nuclear pore
- Vector genome release: Second-strand synthesis completes genome
- Long-term expression: Vector genome persists as episome
- Onset: 2-4 weeks for peak expression
- Duration: Can persist for years in non-dividing cells
- Cell type specificity: Can be engineered with cell-specific promoters
- Immune privilege: CNS has reduced immune surveillance
- Non-pathogenic: No disease-causing capacity; minimal risk of insertional mutagenesis
- Long-term expression: Single treatment can provide years of therapeutic benefit
- Neuronal tropism: Naturally targets neurons and glia
- Safety profile: Well-tolerated in clinical trials
- BBB penetration: Some serotypes (AAV9) can cross with certain delivery methods
- Manufacturing: Scalable production systems available
- Pre-existing immunity: ~60% of population has neutralizing antibodies to common serotypes
- Cargo size limits: Cannot deliver large genes or regulatory elements
- Dose-dependent toxicity: High doses associated with liver toxicity
- Anterior-posterior gradient: Difficult to achieve uniform brain coverage
- D dorsal root ganglion toxicity: Observed with some high-dose CNS deliveries
- Manufacturing complexity: Expensive and challenging to produce at scale
- Immunogenicity: T cell responses can eliminate transduced cells
- AAV-PHP.B: Engineered variant with ~40x better mouse CNS transduction
- AAV-PHP.eB: Further improved CNS transduction
- AAV9: Best characterized for CNS; some BBB crossing ability
- Capsid mutagenesis: Random or directed evolution
- Library screening: In vivo selection for CNS targeting
- Brain shuttle antibodies: Fusing antibodies to AAV capsids
- Masking: Reducing immune recognition while preserving function
No AAV gene therapies are currently approved specifically for neurodegenerative diseases. However, CNS-targeting AAV programs are in various stages:
| Disease |
Programs |
Stage |
| Parkinson's |
12+ |
Phase I/II |
| Alzheimer's |
8+ |
Preclinical/Phase I |
| Huntington's |
6+ |
Preclinical |
| ALS |
5+ |
Phase I/II |
- Spark Therapeutics (Roche): Pioneer in AAV gene therapy
- Voyager Therapeutics: CNS-focused AAV pipeline
- NeuExcell Therapeutics: AAV-based programs for CNS disorders
- Passage Bio: AAV delivery for CNS monogenic disorders
- Biogen: Multiple CNS AAV programs
- Novartis: Acquired AveXis for AAV capabilities
- Pfizer: CNS gene therapy division
- Sanofi: Partnering on rare disease gene therapy
- Catalent: Leading AAV CDMO
- Thermo Fisher: Manufacturing services
- Baxter: Gene therapy manufacturing
¶ Dosing and Delivery Methods
- Direct injection into target brain regions
- Stereotactic guidance for precision
- Limited distribution from injection site
- Injection into cerebrospinal fluid
- Better CNS distribution than intraparenchymal
- Targets spinal cord and lower brain
- Least invasive route
- Requires AAV variants that cross BBB
- Highest systemic exposure
- Positive pressure infusion
- Improved bulk flow distribution
- Being explored for uniform brain coverage
- Continued engineering for enhanced CNS tropism
- Reduced immunogenicity variants
- Redosable systems
- Suspension cell culture systems
- Higher yields
- Reduced costs
- CRISPR delivery for gene editing
- Base editing delivery
- RNA targeting with AAV-delivered Cas13