MCT8 gene mutations produce thyroid hormone (TH) deficiency in brain, causing severe neuropsychomotor abnormalities not correctable by TH treatment. We examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice (Mct8KO). AAV9-hMCT8 or empty vector were injected intraventricularly (IV) and/or intracerebroventricularly (ICV) into postnatal day 1 Mct8KO mice and the active TH, T3, was given for 4 days before tissue collection at post-natal day 28. Compared to IV, ICV delivery produced more hMCT8 mRNA and protein, which was present in various brain regions and localized to the cell membranes. Despite more abundant hMCT8 mRNA and protein with ICV delivery, only IV delivered AAV9-hMCT8 targeted the choroid plexus and significantly increased brain T3 content and expression of the TH-regulated transcription factor, Hairless. These results indicate that MCT8 delivery to brain barriers by IV but not ICV injection is crucial for its proper function. MCT8 has no constitutive activity but acts through an increase in T3 entering brain tissue. The correct hMCT8 isoform along with an optimized delivery method are critical for an effective gene therapy to provide functional MCT8 in the brain of patients with MCT8 mutations.

Resumen del trabajo presentado al MCT8 Symposium: "Current Knowledge, Future Research on Treatment", celebrado en California (USA) del 12 al 14 de enero de 2016.-- et al.

Peer Reviewed