[SMC] Effective Treatment of Colq-Deficient Mice with Adeno-Associated Virus Type Rh74-Mediated Gene Therapy

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Hum Gene Ther. 2025 Oct 8. doi: 10.1177/10430342251386011. Online ahead of print.

ABSTRACT

Mutations in human COLQ, which encodes the collagen-like tail subunit (ColQ) of asymmetrical acetylcholinesterase (AChE), cause congenital myasthenic syndrome (CMS) with deficiency of end plate AChE. A valuable animal model of COLQ-CMS is the Colq-deficient (Colq-/-) mouse, which lacks asymmetrical AChE in skeletal and cardiac muscles. Mutant Colq-/- mice fail to thrive, and many die before reaching maturity. With the aim of developing a treatment for COLQ-CMS, Colq-/- mice were injected at postnatal day 26-29 with three doses of an adeno-associated virus type rh74 carrying full-length human COLQ (AAVrh74-COLQ): 5 × 1013 viral genomes per kilogram (vg/kg) (intravenously [IV]), 1 × 1014 vg/kg (IV), and 2 × 1014 vg/kg (1 × 1014 vg/kg IV + 1 × 1014 vg/kg intraperitoneally). Motor performance was evaluated using rotarod, grip strength, and wire hang tests weekly for 12 weeks. Voluntary ambulation and repetitive nerve stimulation (RNS) were assessed once before euthanasia. Protein and RNA expression of COLQ was measured via immunohistochemistry (IHC) and reverse transcriptase quantitative PCR (RT-qPCR), respectively. Mice treated with AAVrh74-COLQ at 1 × 1014 and 2 × 1014 vg/kg doses showed 100% survival and no adverse side effects. Mice injected with 2 × 1014 vg/kg showed almost full recovery and similar scores to wild type that were significantly higher than vehicle-injected mutants for grip strength (p value

Source: https://pubmed.ncbi.nlm.nih.gov/4105850 ... t9+e462414