Chinese team develops world's first dog model with genetic mutations repeatedly found in autism patients

For the first time, Chinese scientists have developed a model of autism spectrum disorder (ASD) in dogs by using gene-editing technology, a breakthrough that will provide a new avenue for developing medicines in treating the brain disease, the Global Times learnt from the research team.

The team led by Zhang Yongqing from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (CAS), in collaboration with Beijing Sinogenetic Biotechnology Co. and Yale School of Medicine, published its study in Nature's Molecular Psychiatry journal last month.

The researchers used the CRISPR/Cas9 gene editing to mutate the SHANK3 gene whose mutations are one of the most replicated genetic defects identified in autism patients. After nearly eight years of study, the team successfully created multiple lines of beagles that have shown distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings, Zhang told the Global Times.

ASD is a common mental illness in children and adolescents. About one in 100 children has autism, according to the World Health Organization. The mental and neurological disorder is a developmental lifelong condition, affecting an estimated one percent of the population worldwide. Research on those brain diseases relies on appropriate animal models. 

However, despite intensive studies in modeling neuropsychiatric disorders, especially ASD in animals, many challenges remain. 

For example, mice, which have been widely used as a model of autism research, have significant differences in their brain structure, function and behavior compared with humans, which greatly limits the clinical translation of research results, highlighting the urgency to develop other animal models, Zhang said.

Zhang noted non-human primates including monkeys have been used to model ASD in recent years. "I also participated in the modeling of non-human primates including monkeys." Although the structure and behavior of the monkey brain is very similar to that of the human brain, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost, prohibit a wide use of them in preclinical studies, the researcher noted.

The canine model is an appealing alternative because of its complex and effective dog-human social interactions, he said, noting that in contrast to monkeys, dogs have a high reproduction rate and they have comparable drug metabolism to humans. 

Dogs have made great contributions to human health studies worldwide. They have been widely used in human health research, Zhang said. "For example, the safety evaluation of drugs and the safety and effectiveness assessment of medical devices are often carried out in dogs." 

But it is the first time in the world that the model of autism spectrum disorder in dogs has been created, Zhang said, noting that all their researches and experiments are strictly operated in accordance with international norms.

According to the WHO, autism spectrum disorders are a diverse group of conditions. They are characterized by some degree of difficulty with social interaction and communication. Other characteristics are atypical patterns of activities and behaviors, such as difficulty with transitioning from one activity to another, a focus on details and unusual reactions to sensations.

Current treatment of ASD patients includes improving social and life skills, as well as reducing behavioral symptoms such as anxiety and aggression. 

After tens of thousands of years of co-evolution and breeding, the dog is human's closest companion. The most significant biological feature of dogs is their highly developed emotional cognitive function. They are intimate and effective communicators with people. "So the establishment of canine models has great potential for the study of brain diseases in the future, especially in drug evaluation," Zhang said, noting they selected beagles as the test subjects.

They also plan to use dog models to develop new drugs and evaluate the potential for drugs that have been approved by the drug watchdog but have not been used to treat autism. 

In addition, they hope dog models can be used to identify social adjustment interventions and study non-invasive interference strategies such as transcranial magnetic therapy, to improve the autism symptoms.

The researchers also carried out behavioral analysis on mutant dogs. This included using machine learning to analyze tail position and wagging, as well as observing interactions with humans and other dogs.

According to their paper, they found that the dogs "exhibited distinct and robust social behavioral deficits including social withdrawal and reduced social interactions with humans."

In addition, they developed a pupilometer for real-time pupillometry in dogs, which is an eye-tracking technique used to analyze behaviors of experimental subjects. They also published a separate paper back-to-back in the same journal.

The results showed that the pupil response of the mutant dogs was consistent with that of the autistic patients, and the pupils of the mutant dogs were more significantly enlarged under normal sound stimulation conditions, indicating that they were more sensitive to sound, according to the paper.

"The dog model provided us with a new platform and opened a new avenue to carry out mechanistic studies of brain diseases, which may help us accelerate the preclinical research of the disease," Zhang said.

He also stressed that the dog models could also be used to better understand other brain and mental disorders caused by genetic variants, including Alzheimer's. 

"This is just the beginning. I hope that in the next five to 10 years, we can promote brain disease research using dog models, and take full advantage of their unique biological features," Zhang noted.