Taiwanese Team Develops Mouse Model That Displays the Early Stages of Human FAP

A new mouse model capable of displaying the early symptoms of familial amyloid polyneuropathy may help researchers understand mechanisms underlying the disease and test therapies that focus on its initial stages.

The Taiwanese team that created the model wrote about it in the journal Neuropathology and Applied Neurobiology. The title of the article is “Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser.”

One of the early manifestations of FAP is degeneration of sensory nerve cells. This deterioration leads to abnormal sensations, such as pain from normally non-painful stimulation.

FAP patients “frequently perceive enhanced sensitivity or discomfort on exposure to mechanical stimuli that healthy subjects consider innocuous instead of painful,” the researchers wrote. Pain arising from stimulation such as a light touch that most people don’t experience is called mechanical allodynia pain.

Mice with mutations of the TTR gene, which is responsible for FAP, have helped researchers gain insight into mechanisms underlying the disease. But until now no mouse model has been able to replicate FAP’s early pain manifestations.

The Taiwanese researchers came up with a mouse model that can display the early pain symptoms, which they call the TTR-A97S knock-in mouse.

To create the model, they replaced the mouse gene with a human gene. It contained one normal copy of the gene and one with the most prevalent TTR mutation found in Taiwanese FAP patients — TTR-A97S.

The researchers conducted a series of tests to evaluate the model’s potential to be a good representation of the early stages of FAP.

“Given that sensory symptom phenotypes [characteristics] of neurological deficits are early manifestations of FAP and major targets of clinical trials, it is critical to develop an animal model that recapitulates sensory nerve degeneration, along with its physiological and functional consequences,” the researchers wrote.

Their analysis showed that the new model displayed the major initial manifestations of FAP, including nerve pain, less nerve sensation, and less nerve fiber density. The pain included mechanical allodynia pain.

Another characteristic of FAP that the model displayed was harmful amyloid protein deposits occurring alongside sensory nerve degeneration.

The only symptom that the TTR-A97S knock-in mouse failed to display was the movement difficulties seen in FAP patients. But these occur later in the disease, the researchers noted.

This means that the model does a good job of representing the early stages of FAP, the team said.

“Since current medications can only slow the progression of FAP,” they wrote. “Our human TTR-A97S knock-in mouse model provides a platform to develop new therapies targeting early stages of FAP.”