Down Syndrome is the disorder resulting from a partial or complete copy of the 21st chromosome. In fact, another name for Down Syndrome is trisomy 21. It affects nearly 1 in 700 Americans, and crosses all racial and economic boundaries. Down syndrome is an inherently complicated disease to treat with potentially over 300 misappropriated genes on that 21st chromosome.
This poses an exceptional challenge for researchers looking to identify potential treatment targets as well as agents. Fortunately, researchers at Hopkins were able to find a compound that can reverse the symptoms seen in the disorder, pushing science one step closer to finding treatment for Down Syndrome.
Hopkins researchers have been working extensively in collaboration with NIH on Down Syndrome treatments. Their recent breakthrough was conducted using a special mouse model, each carrying a copy of around 100 genes from human Chromosome 21 within its own DNA. These mice have been shown to exhibit many of the symptoms of Down Syndrome we see in humans, and are routinely used in studies regarding the disorder.
One such symptom related with Down Syndrome is an underdeveloped cerebellum, the portion of our brain essential to motor control and spatial awareness. Smaller cerebellum are observed in both affected humans and mouse models. According to previous findings, this may have been caused by the retardation in cell division in precursor cells in the first days of birth.
The growth of the cells is normally determined by a combination of growth factors such as the aptly named Sonic Hedgehog Growth Factor (Shh). Research at Hopkins has shown that when affected mice were treated with Shh pathway activator (SAG) from birth precursor, cell proliferation rates were returned to normal levels.
These researchers studied the effects of this treatment by focusing primarily on the function of two areas of the brain: the cerebellum, where morphological changes were initially observed, and the hippocampus, a common target for Down syndrome therapies due its central role in learning and memory. While it was cerebellum development with the SAG treatment would translate into functional improvements, results proved to be more complicated.
One metric used was the measurement of synaptic activity of a type of neuronal cell type called Purkinje cells located in the cerebellum. However no significant improvements were observed between Down Syndrome mice treated with SAG and those without.
Another metric used to measure cognitive performance used by the researchers was the Morris Water Maze. In these experiments mice are placed in shallow pool with a platform, where they could take a break from swimming. They measured how long it would take for the mice to find the platform. When the platform was visible, all mice – including those that were afflicted and treated with SAG, those that were afflicted and untreated, and those that were euploid, or containing a normal amount of chromosomal material, – performed roughly the same.
However, once the platform was hidden in a maze, the mice took in a number of visual cues around the pool to identify the location of the platform. As the mice perform the task repetitively, the response time diminished.
However, in the test there was a clear distinction between the performance of afflicted and normal euploid mice, where the afflicted mice took longer initially to find the platform and experienced limited improvement compared to the euploid mice.
However, afflicted mice treated with SAG from birth showed dramatic improvement compared to untreated controls and actually performed similarly to the normal euploid mice. When the platform was removed, mice were tested to see if they could remember where that platform was originally located by measuring how much time they spent in that area.
Such a task requires both spatial awareness and memory. Again, the untreated mice performed significantly worse than euploid mice, but afflicted mice that were treated with SAG from birth showed significant improvement and actually performed similarly to the euploid mice.
This improvement suggested that hippocampus may also be positively affected by their SAG treatment. To test whether this was the case, they measured the amplitude of action potentials along neurons, as well as the reliability of neurotransmitter release. They found that SAG treatment increased the synaptic performance of afflicted mice to a point where the events were indiscernible from that of the normal euploid mice. This shows that SAG treatment can at least partially normalize hippocampal physiology as well.
These results suggest that SAG treatment may in fact be an effective treatment to aid in cerebellum and hippocampal development. Not only have they shown its effects on physiology, but they have also demonstrated cognitive gains in certain areas as well. The researchers stress that SAG treatments must be used with caution as the Shh pathway has been shown to be activaated in some tumor types.
However, none of the SAG treated mice in this study showed any evidence for tumor development. In addition it is important to note that this work represents merely one treatment strategy; a multifaceted approach will certainly be necessary for effective treatment of a disease as complex as Down Syndrome.