PubMed · 8041432
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F Zelmanovitz, J L Gross. 1994-08-25. Clinical problem-solving: remembering the ABC's.. https://pubmed.ncbi.nlm.nih.gov/8041432/
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Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here, we report the results of preclinical studies evaluating 24 candidate therapies. RNA sequencing analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglial model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.
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A low maternal serum concentration of pregnancy associated plasma protein-A (MS-PAPP-A) in the first trimester has been suggested as a marker for the presence of a Down's syndrome (DS) fetus. We developed a time-resolved immunofluorometric assay (TrIFMA) for PAPP-A with a sensitivity < 3.9 mIU/l. In the 7-12 gestational weeks interval the median multiples of the median (MoM) was 0.57 (95%-confidence interval; 0.47-0.99) in DS pregnancies (n = 29) and lower than in controls (n = 223) (P < 0.005). The efficiency of MS-PAPP-A alone was evaluated using empirical receiver-operator-characteristics (ROC) and a sensitivity of about 25% was found for a false-positive rate of about 10% in the 7-12 gestational weeks interval. In parameterized ROC analysis a sensitivity of 9% was found for a false-positive rate of 5%. The TrIFMA PAPP-A assay seems to fulfil the quality criteria for an assay to be used in large-scale serum screening for Down's syndrome.