Gene therapy-mediated overexpression of wild-type MFN2 improves Charcot-Marie-Tooth disease type 2A
Bibliographic record
Abstract
Abstract Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor-dominant phenotype. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding Mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 are known to affect mitochondrial dynamics. We previously demonstrated that the mutated MFN2 Arg94Gln further disrupts contacts between the ER and the mitochondria, leading to progressive axonal degeneration. There is no effective therapeutic approach to slow or reverse the progression of CMT2A, and treatments currently under development primarily focus on restoring mitochondrial function. Here, we provide proof-of-concept that neuronal overexpression of wild-type MFN2 (MFN2 WT ) provides therapeutic benefit in transgenic CMT2A mice carrying the mutated MFN2 Arg94Gln . Intrathecal delivery of an AAV9 vector expressing MFN2 WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved following vector injection after the onset of symptoms, rescuing the molecular hallmarks of CMT2A pathology and reversing locomotor. Notably, AAV administration was well tolerated, with no evidence neither of hepatotoxicity nor dorsal root ganglion inflammation. These results establish that boosting MFN2’s levels using gene therapy is a promising therapeutic avenue for CMT2A.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".