Molybdenum cofactor deficiency is an autosomal, recessively inherited metabolic disorder, which, in the absence of an effective therapy, leads to early childhood death due to neurological deterioration. In type A of the disease, cyclic pyranopterin monophosphate (cPMP) is missing, the first intermediate in the biosynthesis of the cofactor, and a biochemical substitution therapy using cPMP has been developed. A comparable approach for type B of the disease with a defect in the second step of the synthesis, formation of molybdopterin, so far has been hampered by the extreme instability of the corresponding metabolites. To explore avenues for a successful and safe gene therapy, knock-in mouse models were created carrying the mutations c.88C>T (p.Q30X) and c.726_727delAA, which are also found in human patients. Recombinant adeno-associated viruses (rAAVs) were constructed and used for postnatal intrahepatic injections of MoCo-deficient mice in a proof-of-concept approach. Singular administration of an appropriate virus dose in 60 animals prevented the otherwise devastating phenotype to a variable extent. While untreated mice did not survive for more than 2 weeks, some of the treated mice grew up to adulthood in both sexes.
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This study was supported by the Deutsche Forschungsgemeinschaft (DFG RE768/18-1). Construction of knock-in mice and gene therapy vectors was performed by commercial entities as indicated in the text. Intellectual property rights are owned by the author, the Universitätsmedizin Göttingen and the Deutsche Forschungsgemeinschaft. I thank Christina Ahlbrecht for invaluable help with the animals and laboratory work.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Nds. Landesamt für Verbraucherschutz und Lebensmittelsicherheit (LAVES), Dezernat 33, Röverskamp 5, 26203 Wardenburg).
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Reiss, J. Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections. Hum Genet 138, 355–361 (2019) doi:10.1007/s00439-019-01992-z