Therapieansätze für Nonsense-Mutationen bei Succinat-Semialdehyd-Dehydrogenase-Defizit
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Beschreibung
SSADH deficiency is a rare, autosomal recessively inherited metabolic disorder, leading to an inadequate conversion of succinic semialdehyde to succinic acid and to an increase of GABA and especially of GHB levels due to a deficit of the NAD+-dependent enzyme succinic semialdehyde dehydrogenase (SSADH). As a consequence, a delay of the motor, mental and language development can be observed, but the symptoms can range from mild to severe. So far, there are no effective therapy options known. Only a mitigation of the symptoms is available, for example by means of improvement of the mobility through physiotherapy and improvement of the language through speech therapy.
Due to the lack of options for treatment, the main goal of this project was to explore new therapeutic approaches for nonsense variants within the SSADH coding region. For this purpose, a variety of effects of the treatment of different nonsense variants (Gln79X, Tyr128X, Gln133X, Lys192X, Trp204X, Ser251X, Arg261X, Arg412X, Gln477X, Arg514X and Tyr519X) was investigated with translational read-through inducing drugs, such as amlexanox, gentamicin and PTC124, as well as with the mRNA-stabilizing drug caffeine, based on Western blot and the SSADH activity assay.
The data revealed that the treatment of the variants with one of the substances amlexanox, gentamicin and PTC124, did not exhibit any systematically reinforced protein expression in the Western blot. In the activity assay, a significant increase of SSADH activity was only evident for the variant Trp204X upon treatment with amlexanox. Likewise, the combination of the above drugs with caffeine led to no significant increase in SSADH activity. In the Western blot, the treatment with amlexanox and caffeine on the variants Gln79X, Lys192X, Trp204X and Arg412X showed a systematically positive result. In the case of the treatment with PTC124 and caffeine on the variants Gln79X, Lys192X and Trp204X, the result was also systematically positive.
Due to the discrepancy between the Western blot and the activity measurement, it is not clear whether the tested substances would be promising for the treatment of patients. Thus, it can be concluded that the treatment of the nonsense variants at SSADH deficiency should take place in a variant-specific manner after prior testing.
Autor*in
Alice-Miriam Zymanczyk
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Amlexanox Coffein Gentamicin PTC124 SSADH SSDD