Controlling Transgene Expression in the Central Nervous System For MRI-Guided Focused Ultrasound Delivery of Adeno-Associated Virus
Bibliographic record
Abstract
Adeno-associated virus (AAV) transgene delivery could provide sustained therapeutic support to the central nervous system (CNS). However, the blood-brain (BBB) and blood-spinal cord barrier (BSCB) impede intravenous delivery of AAVs. Therefore, MRI-guided focused ultrasound (MRIgFUS) was used to facilitate intravenous delivery of non-BBB penetrating AAV serotypes, or AAV9 at a dose approximately 50-fold lower than the systemic minimum, to targeted regions of the CNS. First, AAV9 distribution in the spinal cord tested whether physical differences in the BSCB compared the to the BBB cause alterations in MRIgFUS delivery. Two weeks after MRIgFUS delivery of AAV9 to a 7 mm, unilateral length of the rat cervical spinal cord 36% of oligodendrocytes and 87% of neurons in the FUS-targeted region were transgene-positive. GFP expression was also seen in the liver, heart, and muscle. Thereafter, targeting transgene expression to specific CNS cell types, while preventing expression in peripheral organs was investigated. Specifically, the glial fibrillary acidic protein (GFAP) astrocyte promoter and the neuron-derived synapsin (syn) promoter were used to control expression of green fluorescent protein (GFP). Since AAV9 led to high levels of liver transduction, AAV1/2 and AAV6 were chosen to test transgene expression under the CNS-associated promoters and compared to the constitutive human beta actin (HBA) promoter. To evaluate whether transgene expression can be increased alongside GFAP near Aβ plaque, mosaic AAV1/2 expressing GFP under either the GFAP promoter or the HBA promoter was delivered to TgCRND8 amyloidosis model mice. Under the GFAP promoter, GFP fluorescence intensity, expression volume, and surface area were higher in astrocytes near Aβ plaque compared to Aβ-unassociated astrocytes. The GFAP promoter was astrocyte-specific in the brain, but allowed expression in the liver. Thereafter, AAV6 and AAV1/2 expressing GFP were compared using the syn promoter. Compared to AAV1/2-syn-GFP, AA6-syn-GFP delivery resulted in a two-fold increase in transgene-positive neurons, and over four-fold less liver transduction. The syn promoter prevented transgene expression in the liver, kidney, heart, muscle, spleen, and lung. In conclusion, MRIgFUS-facilitated gene delivery can target both the brain and spinal cord, and AAV6-syn is a promising candidate for liver-detargeted, neuron-specific transgene expression in the CNS.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".