Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease - PubMed
5 hours ago
- #CMT2A
- #gene therapy
- #mitochondria-ER contacts
- Gene therapy using wild-type MFN2 (MFN2WT) improves Charcot-Marie-Tooth type 2A (CMT2A) in mice and motor neurons derived from induced pluripotent stem cells.
- Intrathecal delivery of an AAV9 vector expressing MFN2WT targets motor and sensory neurons, restores ER-mitochondria contacts and mitochondrial morphology, and preserves neuromuscular junction integrity and motor function.
- Therapeutic efficacy is achieved even after symptom onset, with good tolerability and no evidence of hepatotoxicity or dorsal root ganglion inflammation.
- An ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts also corrects CMT2A pathology in vitro and in vivo.
- Restoring ER-mitochondria interplay via gene therapy is a promising therapeutic approach for CMT2A.