Researchers develop minipig model to study juvenile Batten disease

Scientists say miniswine are more translatable to human disease than mice

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers have developed a new minipig model of juvenile Batten disease that recapitulates some key features of the human condition, including vision loss and gait abnormalities.

Despite certain limitations, scientists believe these miniswine are more translatable to the human disease compared with mouse models of juvenile Batten, also known as CLN3 disease.

The pigs ultimately “hold the promise of improving our understanding of CLN3 disease mechanisms and provide a more-relevant setting in which to test therapeutic interventions,” the researchers wrote.

The study, “A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes,” was published in Disease Models and Mechanisms

The most common form of Batten disease, juvenile Batten is caused by mutations in the CLN3 gene. Consequently, certain waste products accumulate inside cells, leading to inflammation and neurodegeneration.

The earliest symptoms, which typically emerge between ages 5-8, usually include vision loss, followed by cognitive decline, loss of motor function, and seizures.

Scientists can study disease mechanisms and potential treatment candidates in preclinical models that house similar CLN3 mutations as those observed in patients.

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New mouse model seen to better mimic survival in juvenile Batten

Mice models offer subtle deficits than typical to patients

While a number of such mouse models exist, differences in anatomy, lifespan, and body size relative to humans limit their ability to accurately reflect the disease. Mouse models tend to have more subtle deficits than what is typically seen in patients.

Larger animal models exist for other forms of Batten disease, such as sheep models of CLN1, CLN5, and CLN6 disease, as well as dog and pig models of CLN2 disease.

Generally, these models exhibit more clinically relevant symptoms of Batten disease, and their longer lifespans allow for more data to be collected, according to researchers.

In the study, the scientists described the development and characterization of a miniature pig, or miniswine, model of CLN3 disease. These pigs were genetically engineered to house the most common disease-causing mutation found in patients, called del-ex7/8.

The scientists noted pigs have certain characteristics that may make them better models for human disease than mice. Their brains are more similar to human brains, and they also are more similar in size and physiology to humans.

By 30 months (about 2.5 years) of age, the CLN3 mice exhibited significant degeneration of the retina, the back part of the eye needed for vision, and evidence of extreme visual impairments.

This age in pigs roughly correlates to older adolescence in a human, the scientists noted. While emergence of this symptom can vary in patients, it often emerges at a slightly younger age.

The CLN3 model exhibited limited dysfunction in tests of cognition, but the miniswine did show robust motor abnormalities, with significantly altered gait relative to healthy or wild-type animals.

Pigs have altered stability, much like CLN3 patients

Further analyses revealed that the CLN3 pigs seemed to have altered stepping and center-of-pressure dynamics in their front feet, consistent with the decreased stability observed in patients.

The team noted that visual and motor changes observed in the pig model are more robust and consistent with patients’ disease expression than those seen in mouse models.

Other clinical factors, such as body condition, weight, social and feeding behavior, general activity levels, and sleep were similar between CLN3 and wild-type animals. No seizures were observed.

Given the long natural lifespan of these pigs, no differences in survival were observed between CLN3 and wild-type animals with up to four years of follow-up.

ATP synthase subunit C, a waste product known to accumulate in juvenile Batten, was found to accumulate through multiple brain regions in the CLN3 pigs starting very early in life.

Other characteristic signs of juvenile Batten in brain tissue, including neuroinflammation and the degeneration of certain nerve cell populations also were  observed, but the pattern was not as robust as that seen in patients.

While the findings overall indicate the swine model may have better translatability to the human condition than mice,  it does not perfectly recapitulate features of juvenile Batten, the scientists noted.

Nevertheless, researchers believe the new model will be useful in the search for new CLN3 disease therapies.

“Using an animal model that is physiologically and anatomically similar to humans should increase the likelihood that a treatment will be useful, and eventually, be  approved for clinical trials,” they wrote. “Ultimately, we are all trying to find better therapeutics that will successfully treat individuals with Batten disease.”