[Background]: MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. In this proof of concept study, 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). [Methods]: AAV9 vectors delivering long and/or short hMCT8 protein isoforms or an empty vector were injected intravenously (IV) and/or intracerebroventricularly (ICV) into postnatal day 1 Mct8KO and wild type (Wt) mice. T3 was given daily for 4 days before post-natal day 28, at which time brains were collected after perfusion to assess increase in T3 content and effect on the T3-responsive transcription factor, Hairless. [Results]: Increased pup mortality was observed after IV injection of the AAV9-long hMCT8 isoform, but not after injection of AAV9-short hMCT8 isoform. Compared to IV, ICV delivery produced more hMCT8 mRNA and protein relative to the viral dose, which was present in various brain regions and localized to the cell membranes. Despite production of 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 Hairless. [Conclusions]: 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. Increasing MCT8 expression on brain cells membranes, including neurons, is insufficient to produce an effect without increase in brain T3 content. 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, celebrado en Los Angeles (California-USA) del 4 al 6 de enero de 2017.

Peer Reviewed