Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

Abstract

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased T3 levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

A novel strategy for deliveringNiemann‐Pick typeC2proteins across the blood–brain barrier using the brain endothelial‐specificAAV‐BR1virus

“…In addition to the desired transduction of BECs, we noticed the capability of the AAV-BR1 vector to cross the BBB both in vitro and in vivo and an ability to transduce neurons in vivo. The same phenomenon has previously been reported upon intravenous administration of the AAV-BR1 vector, albeit not to the same extent (Dogbevia et al, 2020;Körbelin et al, 2016;Sundaram et al, 2021).…”

“…Then we wanted to examine the distribution and potential of the AAV-BR1 vector in healthy BALB/c mice, as this viral vector, to our knowledge, never have been investigated in this specific inbred mouse strain. Previous studies with the AAV-BR1 vector have included FVB/N and C57BL/6 mice (Carroll et al;2020;Chen et al, 2020;Dogbevia et al, 2017Dogbevia et al, , 2020Ivanova et al, 2021;Körbelin et al, 2016;Park et al, 2021;Sundaram et al, 2021). For that purpose, two different constructs were designed and used to study the in vivo distribution of the AAV-BR1 vector.…”

Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates

“…In addition, capsid entry into other cell types may induce an immune response, creating a confounding effect. Similar problems also apply to the previously-reported BR1 endothelial variant, BR1 transduces a large number of neurons and astrocytes other than endothelial cells (Körbelin et al 2016;Sundaram et al 2021). With the increasing numbers of engineered AAVs reported, there are also increasing examples showing their potential distinct tropism across species (Chen et al 2022;Challis et al 2022), emphasizing the necessity for the testing of engineered variants in different species especially non-human primates.…”