TY - JOUR
T1 - AAV9-MCT8 Delivery at Juvenile Stage Ameliorates Neurological and Behavioral Deficits in a Mouse Model of MCT8-Deficiency
AU - Liao, Xiao Hui
AU - Avalos, Pablo
AU - Shelest, Oksana
AU - Ofan, Raz
AU - Shilo, Michael
AU - Bresee, Catherine
AU - Likhite, Shibi
AU - Vit, Jean Philippe
AU - Heuer, Heike
AU - Kaspar, Brian
AU - Meyer, Kathrin
AU - Dumitrescu, Alexandra M.
AU - Refetoff, Samuel
AU - Svendsen, Clive N.
AU - Vatine, Gad D.
N1 - Funding Information:
This research was supported by grants from the Sherman Family Foundation, the Board of Governors Regenerative Medicine Institute at Cedars-Sinai Medical Center to C.N.S., the Israel Science Foundation grant 1621/18 and the Ministry of Science and Technology (MoST), Israel grant 3-15647 to G.D.V. This work was supported in part by grant DK15070 from the National Institutes of Health (USA) to S.R.
Funding Information:
The authors would like to thank Dr. Soshana Svendsen for critical writing and editing. Biostatistical support was received from the Center for Research Support (‘‘HALEV’’), Faculty of Health Sciences, Ben Gurion University of the Negev and by the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai.
Publisher Copyright:
© Copyright 2022, Mary Ann Liebert, Inc., publishers 2022.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-Associated virus serotype 9 (AAV9)-based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-Transporting polypeptide 1c1 (Oatp1c1)-/- double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-Term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.
AB - Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-Associated virus serotype 9 (AAV9)-based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-Transporting polypeptide 1c1 (Oatp1c1)-/- double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-Term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.
KW - MCT8
KW - gene therapy
KW - thyroid hormone cell transport
UR - http://www.scopus.com/inward/record.url?scp=85134257407&partnerID=8YFLogxK
U2 - 10.1089/thy.2022.0034
DO - 10.1089/thy.2022.0034
M3 - Article
C2 - 35350867
AN - SCOPUS:85134257407
SN - 1050-7256
VL - 32
SP - 849
EP - 859
JO - Thyroid
JF - Thyroid
IS - 7
ER -
