368. Advances in Fragile X Gene Therapy Using Adeno-Associated Viral Vectors Coding for the Fragile X Mental Retardation Protein
Bibliographic record
Abstract
Fragile X syndrome (FXS) is a severe debilitating neurodevelopmental disorder characterized by a loss of proper translational control at the synapse. In FXS, an aberrant CGG trinucleotide expansion upstream of the Fragile X Mental Retardation Protein (FMRP) gene causes drastic downregulation of this translational modulator. The absence of FMRP impairs synaptic plasticity and leads to mental retardation and autistic spectrum-related phenotypes. To correct this neurological disorder we recently devised an adeno-associated viral (AAV) vector encoding FMRP where its cellular tropism was controlled by the neuron-specific synapsin promoter. Following intracerebroventricular (i.c.v.) injection in neonatal Fmr1 KO mice, transgene expression remained stable for over 7 months in terminally differentiated neurons. The FMRP transgene corrected PSD-95 protein hypo-expression in the cortex of Fmr1 KO animals, as well as lowered MeCP2 protein over-expression. Behavioral endophenotypes including hyperactivity, non-social anxiety, pre-pulse inhibition, repetitive stereotypies, and social dominance were fully or partially corrected using this viral construct. We combined i.c.v. injection with additional injections into the parenchyma of refractory brain regions to achieve wider transduction, while avoiding potentially pathological transgene over expression effects. This ongoing translational study enables us to determine the proper cellular tropism and the range of FMRP expression required for rescue, as well as the brain region dependent correlation of autistic behaviors implicated in FXS neuropathology. These findings are relevant to gene therapy strategies for treating human FXS, as well as other neurodevelopmental disorders.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".