Prenatal administration of novel compound treats Down syndrome in mice [PreClinical]

1. A chemical library screen identified a compound (termed altered generation of neurons, or ALGERNON) that promoted the proliferation of neural stem cells (NSCs) isolated from a mouse model of Down syndrome (DS).

2. In a mouse model of DS, prenatal treatment with ALGERNON restored neurogenesis and normalized cognitive behaviors.

Evidence Rating Level: 2 (Good)

Study Rundown: DS is the most common genetic cause of intellectual disability and is thought to be due to prenatal defects in neurogenesis. Because the impairment arises during embryonic development, this study aimed to identify a prenatal therapy to restore neurogenesis.

A variety of compounds were assessed for their ability to promote the growth of NSCs isolated from a DS mouse model. Further testing on one compound identified in the screen showed that the compound selectively inhibited DYRK1A, a protein that inhibited NSC proliferation through inducing the degradation of cyclin D1. The compound, named ALGERNON, was administered to pregnant DS model dams. Treatment with ALGERNON prevented cortical thinning in the embryos. Additionally, DS offspring that were prenatally treated with ALGERNON were assessed for behavioral abnormalities. The treated offspring demonstrated improved performance on tasks that measured spontaneous exploration behavior and spatial memory. Side effects were not observed in treated offspring.

This study showed the efficacy of prenatal ALGERNON treatment in improving DS neurogenesis and behavior, as well as a lack of treatment side effects. This study highlights a new potential therapeutic approach for fetuses diagnosed with trisomy 21. Future studies will need to assess the safety and efficacy of this therapy in humans.

Click here to read the study in PNAS

Relevant Reading: Prenatal treatment of Down syndrome: a reality?

In-Depth [animal study]: NSCs were isolated from Ts65Dn DS model mice and treated with compounds from a chemical library. The effects of the compounds on NSC growth were measured by the cells’ BrdU incorporation. One compound significantly increased NSC proliferation (p<0.05). An in vitro kinase panel demonstrated that this compound selectively inhibited DYRK and CLK family proteins, with specific inhibition of DYRK1A activation. To assess the role of DYRK1A in NSC proliferation, a GFP-DYRK1A plasmid was generated and introduced into cultured NSCs. Overexpression of DRYK1A was found to inhibit NSC proliferation (p<0.05). Next, shRNA knockdown of DRYK1A expression resulted in the upregulation of cyclin D1. These experiments showed that DYRK1A regulated NSC proliferation via cyclin D1 expression.

Ts1Cje DS model mice were orally administered 4 mg/mL of the compound for 10 days, and neurogenesis in the dentate gyrus of the hippocampus was assessed through BrdU expression. Treated mice demonstrated an increase in neurogenesis (p<0.05), therefore the compound was named ALGERNON.

ALGERNON was administered to pregnant dams with Ts1Cje trisomy embryos. Compared to vehicle-treated embryos, ALGERNON-treated embryos did not show thinning of the cortical plate and intermediate zone (p<0.05). Finally, cognitive behavior was assessed in Ts1Cje offspring from ALGERNON-treated dams. In a Y-maze task designed to assess spontaneous exploration behavior, treated mice showed improved scores compared to control DS mice (p<0.05). Treated mice also demonstrated improved learning as measured by the Barnes maze, a task used to assess hippocampus-dependent spatial memory. Administration of ALGERNON did not affect other attributes of the offspring, including body weight, rectal temperature, and grip strength.

Image: PD

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