Determine the type of research first
|
Type |
Priority |
Common Misunderstandings |
|
Local expression |
Brain region, cell type, diffusion radius, needle track control |
Extrapolate local high expression to whole-brain ability |
|
Retrograde tracing |
Accessibility of projection terminals, retrograde capsid, direction and synaptic specificity |
Equating retrograde uptake across synapses |
|
Whole-brain/widely expressed |
Species/strain, BBB receptors, intravenous dose and hepatic off-target |
Directly copy the PHP capsid |
|
CSF delivery |
Intrathecal/cisternal/ventricular pathways, meninges and DRG exposure |
Only look at brain tissue fluorescence and ignore neurotoxicity |
Situations when neural projects must be upgraded
- Engineering capsids across the blood-brain barrier or NHP project.
- Study on the safety of CSF high dose, long-term expression or sensory nerves.
- Transsynaptic tools, cytotoxic effectors, long-term calcium/voltage sensor expression.
- Projects that require cross-strain, cross-species replication or clinical transformation.
Recent evidence shows that receptor reprogramming can significantly improve brain delivery, but this advantage is tied to receptor expression and model selection; neurological projects should consider brain area coverage, cell types, liver/peripheral off-targeting and DRG safety as concurrent endpoints. [15-3 to 15-5]
References for this chapter
[15-1] Tervo DGR, et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron. 2016;92:372-382. [H]
[15-2] Deverman BE, et al. Cre-dependent selection yields AAV variants for widespread adult brain gene transfer. Nat Biotechnol. 2016;34:204-209. DOI:10.1038/nbt.3440. [H]
[15-3] Goertsen D, et al. Brain-wide AAV capsid variants with decreased liver targeting in mouse and marmoset. Nat Neurosci. 2022;25:106-115. DOI:10.1038/s41593-021-00969-4. [H]
[15-4] Ling Q, et al. AAV-based in vivo gene therapy for neurological disorders. Nat Rev Drug Discov. 2023;22:789-806. DOI:10.1038/s41573-023-00766-7. PMID:37658167. [N/H]
[15-5] Huang Q, et al. Human transferrin receptor-binding AAV for brain-wide delivery. Science. 2024;384:1220-1227. DOI:10.1126/science.adm8386. [N]