Adeno-associated virus (AAV) vectors are a core delivery technology for gene therapy in neurodegenerative disease because they can support durable expression in post-mitotic neural cells while remaining substantially less pathogenic than many alternative viral systems.[1][2] Their practical utility in CNS disease depends on capsid tropism, route of administration, immune profile, and manufacturing scalability.[1:1][3]
AAV platforms are used across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease programs to deliver gene replacement, gene silencing, neurotrophic support, or genome-editing cargo.[1:2][4]
| Serotype | Tropism | Blood-Brain Barrier | Applications |
|---|---|---|---|
| AAV9 | Neurons, astrocytes | High | Preferred systemic CNS delivery |
| AAVrh.10 | Neurons, microglia | Moderate | Preclinical and translational CNS targeting |
| AAVrh.8 | Neurons | Moderate | Motor neuron applications |
| AAV2 | Neurons | Limited | Historical direct-injection programs |
| AAV-PHP.B | Pan-neuronal in mice | Very high in mice | Mouse engineering studies |
| AAV-PHP.S | Peripheral neurons | High | Peripheral sensory neuron targeting |
| Target | Approach | Stage | Vector |
|---|---|---|---|
| Amyloid-beta production | BACE1 silencing | Preclinical | AAV9 |
| Amyloid clearance | Antibody / degrading enzyme delivery | Preclinical | AAV9 |
| Tau protein pathology | MAPT-lowering approaches | Preclinical | AAV9 |
| Neurotrophic support | BDNF, NGF | Early clinical | AAV2 |
| Target | Approach | Stage | Vector |
|---|---|---|---|
| Dopamine synthesis | AADC gene transfer | Clinical | AAV2 |
| Neuroprotection | GDNF, neurturin | Clinical | AAV2 |
| Alpha-synuclein | SNCA silencing | Preclinical | AAV9 |
| Mitochondrial quality control | PINK1 / Parkin support | Preclinical | AAV9 |
| Target | Approach | Stage | Vector |
|---|---|---|---|
| SOD1 | RNA silencing | Clinical / translational | AAVrh.10 |
| C9orf72 | Editing or repeat-targeting approaches | Preclinical | AAV9 |
| TDP-43 | Modulation of aggregation / expression | Preclinical | AAV9 |
| Target | Approach | Stage | Vector |
|---|---|---|---|
| Mutant HTT | RNAi / miRNA | Clinical / translational | AAV5 |
| Neurotrophic support | BDNF | Preclinical | AAV9 |
| Mutant huntingtin protein | CRISPR-based editing | Preclinical | AAV9 |
The study of Aav Vectors In Neurodegenerative Disease Gene Therapy has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
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Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clinical Microbiology Reviews. 2008;21(4):583-593. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Hudry E, Vandenberghe LH. Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality. Neuron. 2019;101(5):839-862. ↩︎ ↩︎ ↩︎
Tabrizi SJ, Leavitt BR, Kordasiewicz H, et al. First-in-Human Study of AAV5-miHTT Gene Therapy for Huntington's Disease. Annals of Neurology. 2022;91(4):465-480. ↩︎ ↩︎
Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122(1):23-36. ↩︎ ↩︎