New study allows scientists to test therapeutics for rare disease affecting young children — ScienceDaily

For the first time, scientists can test therapeutics for a group of rare neurodegenerative diseases affecting infants and young children thanks to a new research model developed by scientists at the University of Wisconsin-Madison.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases caused by genetic mutations. They cause tens of thousands of children to develop increased muscle tone in their lower extremities, causing weakness in their legs and ultimately affecting their ability to crawl or walk.

“Children who have these mutations as young as six months of age are showing signs of disease,” says Anjon Audhya, a professor in UW-Madison’s Department of Biomolecular Chemistry. “Between the ages of two and five, these children become wheelchair bound and unfortunately never walk.”

Audhya explains that many scientists have not researched spastic paraplegia because there was no good model to study the origins of the disease or to test therapeutics. Previous mouse models didn’t work because the neural pathways that carry movement-related information around the body seem too different from those in humans, and researchers have yet to conduct human clinical trials.

Audhya worked with an interdisciplinary team of UW-Madison researchers to study a specific mutation that causes HSP in young children. They then used what they learned to create a better model – in rats.

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The mutation chosen by the researchers acts on a protein called the Trk-fused gene, or TFG. Healthy TFG proteins work in nerve cells, or neurons, to transport other proteins from one part of the cell to another. A neuron’s job is to transmit messages in the form of electrical signals between the brain and the rest of the body.

The proteins that rely on TFG for their transport keep these neural pathways healthy and help control which electrical signals the brain sends to the body and which signals to inhibit. By balancing the right levels of stimulation, neurons can control movements such as B. the contraction of the leg muscles involved in walking.

In young children with a mutation on their TFG gene, neuronal proteins don’t move efficiently through their nerve cells. According to Audhya, this can create an imbalance in electrical stimulation that allows an abundance of electrical signals to be sent to the lower extremities, resulting in increased muscle tone. The excessive muscle tone leads to a loss of motor skills over time.

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“You can imagine if you stretch your leg really hard and put all your energy into tensing that muscle, it’s really hard to move it,” says Audhya, who is also Senior Associate Dean for Basic Science, Biotechnology and Graduate Studies in the UW School of Medicine and Public Health.

In search of a working model, the researchers turned to rats to help these children. The team used CRISPR gene-editing technology to create the mutations that lead to HSP in rat embryos. This allowed them to study the course of the disease from early development and monitor the progression of symptoms after birth.

Not only are the rats’ neural pathways closer to those of humans, but the researchers also found that symptoms developed in rats similar to those in children with HSP. It also happened so quickly that scientists should be able to easily test the feasibility of potential therapeutics.

“Exercise was the only therapy available for these patients, and that’s really unsatisfactory,” says Audhya. “I think we’ve made a big leap forward by having just one model that you can use to test different hypotheses. That’s big from my point of view.”

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The intricate details of biomolecular chemistry may seem mundane to some, but fundamental research like this fascinates Audhya. It wasn’t until he received a grant from the Spastic Paraplegia Foundation that allowed him to interact with HSP patients that he fully understood the potential impact his work could have.

“These are population groups that are underserved. A pharmaceutical company is unlikely to spend large resources on such a small affected population. Instead, they will focus on diseases like Alzheimer’s and Parkinson’s,” he says. “So I felt like this is a disease that’s being widely overlooked, underinvested in, and here’s an area where we can make a difference.”

Audhya said he hopes this new model will inspire more scientists to study HSP to improve understanding of how the disease develops and eventually improve access to therapeutics to help children living with it.

This research was supported by grants from the National Institutes of Health (R35GM134865, R01NS124165, and R21NS120386)..