Defining neurogenic niche proteome helps identify key regulators of neurogenesis
This study first used rodents and then created human neurons from patient stem cells. The scientists found that the repeat and its translation in the beginning of the Fragile X gene slow down production of the Fragile X protein, which is important in learning and memory. However, when neurons are stimulated, this repeat translation goes away and the Fragile X protein levels increase at synapses (the connections between nerve cells), suggesting that the repeat and its translation regulate this local protein production.
Armed with this discovery about how the repeat functions normally, the team worked with Ionis Pharmaceuticals to develop an antisense oligonucleotide (ASO), a short strand of modified DNA that can specifically target the transcripts of a defective gene to correct an abnormality. Ionis' ASOs are designed to bind precisely with RNA, halting the process of creating a disease-causing protein which could block translation of expanded Fragile X repeats that are toxic to neurons and cause human disease.
This ASO has produced two remarkable results. First, it decreased the toxicity that these repeats caused in rodent and human neurons. Second, this blockade of repeat translation triggered a big increase in the Fragile X protein, whose loss causes Fragile X syndrome. "The results suggest that we have simultaneously corrected two of the big problems that happen in Fragile X-associated disorders," Todd says.
This research offers a novel pathway forward to treatments in this class of neurological diseases.
"To develop a new treatment strategy, we really needed to understand the native biology of how these repeats work and why they are there in the first place," says Todd. "The study was done in dishes, and so there is still a long way before it can be tried in patients, but advancing our understanding of normal nerve cell biology is a crucial step to find cures."
These results were published in Nature Neuroscience on February 17, 2020. Source:
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