The mini pig model of Huntington’s disease not only has a similar brain anatomy to humans, but also shows the slow and age-dependent neurodegeneration and weight loss that’s characteristic of the disease, according to a recent study.
These features make it an advantageous model to use in preclinical studies of Huntington’s targeted therapies, researchers said.
The study, “Transgenic minipig model of Huntington’s disease exhibiting gradually progressing neurodegeneration,” was published in the journal Disease Models & Mechanisms.
Huntington’s disease, which mainly affects the brain, is associated with loss of neurons in specific brain regions (mainly the basal ganglia and cortex), loss of myelin (the protective sheath around nerve cells that allows rapid communication between neurons), microglia activation, as well as dysfunction in mitochondria (the cell’s “powerhouses”), and oxidative stress.
Microglia are the immune cells of the central nervous system (the brain and spinal cord). Oxidative stress is an imbalance between the production of potentially harmful free radicals and the ability of cells to detoxify them, which can lead to cellular damage.
Adequate animal models are crucial to evaluate the potential benefits of an investigational therapy, and the more similar the animal model is to humans (in terms of anatomy, disease features, and underlying mechanisms), the more likely the preclinical results will be reflected in clinical trials.
While mouse models are the primary disease models used in preclinical studies, the “rodent’s small brain size, differences in neuroanatomy relative to humans and short life span limit their application for detailed modelling of the [disease-associated] features of human neurodegenerative diseases,” the researchers wrote.
Larger animal models, such as non-human primates, sheep, and pigs (including mini pigs), are considered “closer” models to humans to evaluate a therapy’s safety and effectiveness over time. They can be used between rodent models and human patients to provide more relevant information before proceeding to expensive clinical trials.
Mini pigs have a relatively large brain with similar anatomy to humans, a relatively long life span (12 to 15 years), comparable weight (70 to 100 kg) to humans in adulthood, as well as relatively low cost and fewer ethical issues than other large models.
Previous studies showed that the mini pig model of Huntington’s disease — mainly between two and four years of age — had motor and cognitive function decline, mitochondrial dysfunction, and other markers of neurodegenerative progression.
In addition, this model was used in preclinical studies of the investigational gene therapy AMT-130, being developed by uniQure. The therapy was shown to have widespread and sustained distribution, and considerable effectiveness in this model.
However, a detailed characterization of this Huntington’s mini pig model, especially in older pigs, remains incomplete.
Therefore, researchers in Czech Republic set out to characterize the disease-associated features of this model as animals aged.
They analyzed the animals’ weight loss — a hallmark of Huntington’s progression — over time (from 1 to 7 years of age) and important neurodegeneration markers in the brain at 48 months (four years) and 60 to 70 months (five to nearly six years).
Results showed that there was a significant weight loss in mini pig females, 6 to 7 years old, compared with healthy age-matched females, but this difference was not significant between diseased and healthy boars of that age.
This gender-specific result may be due to the fact that mature females “are generally heavier and tend to have a greater appetite, therefore a defect in food intake is easier [to detect],” the researchers wrote.
The team also found several markers of neurodegeneration, with signs of progression over time, in mini pigs that were 4 years old and 5 to 6 years old. These markers included accumulation of different forms of mutant huntingtin protein, loss of myelin, and neuronal dysfunction followed by significant neuronal loss in disease-associated brain areas.
Compared with healthy mini pigs, the brains of mini pigs with Huntington’s also showed increased microglia activation (along with lower levels of immunomodulatory and anti-inflammatory molecules and higher levels of pro-inflammatory molecules), followed by a significant higher activation of astrocytes.
While astrocytes (star-shaped nerve cells) are known to provide support to neurons, several studies have shown that inflammatory conditions may turn them into harmful A1 astrocytes, which instead trigger neurodegeneration.
The researchers noted that since they did not specifically analyze A1 astrocytes, further studies are necessary to confirm the hypothesis that their “detection of activated astrocytes reflects a higher production of harmful A1 astrocytes.”
Overall, these findings were consistent with previous studies in younger mini pig models of Huntington’s, as well as data from mouse models of the disease.
“Importantly, the slow progression of the [Huntington’s] mini pig model and the availability of disease biomarkers can be instrumental in the evaluation of [Huntington’s] treatment efficacy,” the researchers wrote.