Pharmacological chaperone testing for enu1/1 and Th-ki mice (copy)
Phenylketonuria (PKU) and tyrosine hydroxylase deficiency (THD) are genetic neurometabolic disorders cause by mutations in phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), respectively. Liver PAH and brain TH belong to the same enzyme-family of aromatic amino acid hydroxylases and share similar function and structure but present different substrate specificity. Investigations, as the one related to this application, benefit of parallel assessment of effects in PAH and TH and of synergistic studies on PKU and THD models since PKU patients show reduced TH activity and ligands might show binding to both enzymes (Calvo et al. 2010, J Neurochem 114:853-63).
The present application relates to the treatment of Enu1/1 and Th-ki mice with the cofactor tetrahydrobiopterin (BH4) and pharmacological chaperone-based therapies with potential for treatment of PKU and THD. The compounds have been tested before and found to have no toxicity in cell cultures and normal mice.
Transgenic mice with mutations PAH (Enu1/1; PKU mutation p.V106A) and TH (Th-ki; mutation p.R233H, equivalent to human p.R202H, present in THD patients in Bergen treated by Prof. Laurence Bindoff, Clin1, UiB) have been produced together with Prof. Beat Thöny, Univ. Zürich, and Prof. Bindoff, and have been previously studied at the Univ. of Zurich, Zwitzerland, from where they were imported to UiB-Animal facility, BBB, autumn 2015. The adaptation has been satisfactory and we are now completing the breeding to obtain enough homozygous Enu1/1 and Th-ki for the treatment assays.
The present application relates to the treatment of Enu1/1 and Th-ki mice with the cofactor tetrahydrobiopterin (BH4) and pharmacological chaperone-based therapies with potential for treatment of PKU and THD. The compounds have been tested before and found to have no toxicity in cell cultures and normal mice.
Transgenic mice with mutations PAH (Enu1/1; PKU mutation p.V106A) and TH (Th-ki; mutation p.R233H, equivalent to human p.R202H, present in THD patients in Bergen treated by Prof. Laurence Bindoff, Clin1, UiB) have been produced together with Prof. Beat Thöny, Univ. Zürich, and Prof. Bindoff, and have been previously studied at the Univ. of Zurich, Zwitzerland, from where they were imported to UiB-Animal facility, BBB, autumn 2015. The adaptation has been satisfactory and we are now completing the breeding to obtain enough homozygous Enu1/1 and Th-ki for the treatment assays.