17. Gene Therapy Strategies to Treat Fragile X Syndrome
Bibliographic record
Abstract
Fragile X syndrome (FXS) is a severe debilitating neurodevelopmental disorder of the autism spectrum that results from an aberrant trinucleotide repeat extension in the 5’ region of the FMR1 gene. This extension pathologically reduces or eliminates the expression of the fragile X mental retardation protein (FMRP). FMRP is known to be a scrupulous translational modulator at the synapse and is also known to stabilize and traffic mRNAs important for proper neurological functions. We utilized C57/BL6 mice with a knock-out of the Fmr1 gene (FMRP-KO) in this study because this mouse model reproduces many of the behavioral phenotypes seen in human Fragile X patients. We used adeno-associated viral vectors (AAV) serotype 2/9, which contains the inverted terminal repeats of serotype 2, the human neuron specific synapsin promoter and the largest isoform of FMRP (isoform 1), as well as downstream woodchuck hepatitis virus post-transcriptional regulatory element and a poly A site to elevate mRNA stability, in order to re-introduce FMRP in the brain of neonatal FMRP KO mice. This vector, as well as a cognate null vector containing no transgene used as a control, were administered via bilateral intra-cerebroventricular injections at different early postnatal time points in wild type (WT) and FMRP-KO mice. AAVs were produced and purified by the University of Pennsylvania Vector Core facility. We also investigated whether FMRP overexpression in WT mice could induce behavioral changes. We tested the treated mice in an array of behavioral tests to monitor changes in autism-associated behaviors such as repetitive stereotypical motions, hyperactivity, deficits in social interaction, and general anxiety. Long term FMRP transgene expression was confirmed by immunocytochemistry and quantitative western immunoblotting where strong forebrain and neuron-specific expression was observed. Overall, we observed partial to full amelioration of certain fragile X phenotypes such as motor activity, sensorimotor gating and open field latency in FMRP-KO mice injected with the AAV-FMRP vectors. Also other observations points towards possible pathological effects due to FMRP overexpression in the forebrain of WT mice; an important consideration for future gene therapy of human FXS. These results show that the time of neonatal injection and the total number of AAV particles administered during intra-cerebroventricular injections can affect the efficacy, distribution of transgene expression, and ultimately, the successful reversal of abnormal behaviors.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".