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Hum Genet. 2019 Feb 27. doi: 10.1007/s00439-019-01992-z. [Epub ahead of print]

Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections.

Author information

1
Institut für Humangenetik der Universitätsmedizin Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany. jreiss@gwdg.de.

Abstract

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.

PMID:
30810871
DOI:
10.1007/s00439-019-01992-z

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