Genetically modified monkeys created for study of autism spectrum disorders

Researchers have genetically engineered monkeys to show autism-like behaviors, in order to further understand autism spectrum disorders and work towards treatments. The only available animal models for studying autism use rodents, which are of limited use for understanding complex disorders. In a Nature paper, the researchers describe how introducing the human gene MECP2 into the genome of macaques caused behavioral changes that were passed down to offspring, including repetitive movements, anxiety and decreased social interaction.

 

Dr. Melissa Bauman, Assistant Professor, Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Davis (webpage):

Expertise: animal models of autism, how maternal immune system changes alter neural development in offspring

“This study is an important extension of groundbreaking research carried out in mouse models of MECP2 disorders which have autism like characteristics.  Mouse models have many advantages, such as low cost, the ability to generate large sample sizes and to carry out extensive pilot work quickly.  However, given that Autism Spectrum Disorder (ASD) is uniquely human disorder characterized by deficits in complex behaviors, there are limitations in relying solely on mouse models.  The Liu et al., paper evaluates the role of MECP2 in the macaque monkey, a non-human primate model that exhibits behavioral and neuroanatomical complexity more similar to humans. Although the social impairments exhibited by the transgenic MECP2 monkeys are compelling, the paper would be strengthened by additional measure of social functioning relevant to autism (i.e., eye- tracking studies etc.) to maximize translational potential of this model.  Nonetheless, this is an important step in utilizing transgenic non-human primate models to evaluate therapeutic strategies for neurodevelopmental disorders.

“Studying the genetics of autism is a daunting task.  The Liu et al., paper makes important contributions to our understanding of the role of MECP2 in neurodevelopment, but this is just one piece of the puzzle.  Studies of individual genes and pathways, as well as genome-wide approaches are needed to fully understand genetic contributions to complex human brain diseases, such as ASD.  Preclinical research in animal models is an essential component of this integrated approach.

“Strong evidence indicates that causes of ASD include both genetic and environmental factors.  Previous non-human primate models have focused on environmental risk factors, and in particular, prenatal immune based risk factors.  The transgenic monkey model established by Liu et al., in combination with recent advances in nonhuman primate gene-editing methodologies, opens the possibility to explore genetic risk factors in a species more closely related to humans.

“Many pharmacological interventions developed in mice to treat human disease ultimately fail. Cross-species approaches that capitalize on the strengths of rodent, and ultimately nonhuman primate, models are more likely to lead to successful therapeutic approaches for complex brain disease. Ultimately, we will need to understand how genetic and environmental risk factors converge, and this study is a critical step towards that goal.”

 

Dr. Eric J. Vallender, Associate Professor, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center (webpage):

Expertise: comparative evolutionary genetics, with a primary focus on non-human primate neurogenetics; development of non-human primate models of human disease

“It is true that a major challenge for the study of autism spectrum disorders is the lack of proper animal models. Beyond the genetics question, it isn’t clear what an “autistic” mouse or rat would look like. So many of the characteristics that we define as diagnostic of autism, deficits in communication or in social interactions, are very difficult to accurately observe in animals, especially rodents.

“Autism is an incredibly complex disease and it does not have a single underlying biological cause. While it certainly has a genetic component to it, a full understanding of the genetics is still a long way away. Some cases of autism do derive from relatively simple genetic events. Mutations in MECP2 and the duplication of MECP2 are only one of these myriad causes. The authors, however, are careful and correct in the paper to describe this animal model as a model of MECP2 duplication, which shows autism-like behaviors, but not to generalize their findings to all autism cases.

“The phenotypes that they are describing at least have some face validity though more work will obviously be required. For instance, repetitive motor behaviors and anxiety-like behaviors can be caused by many things and “decreased social interaction” is always tricky to both observe and quantify and to interpret. That said, they have created an excellent model of MECP2 duplication syndrome. This is not trivial and can be a major step forward for understanding neurodevelopmental disorders. It is one model of autism, but it isn’t the only model of autism.

It is too early to say whether this model may lead to development of therapies. Even if we do develop a drug I’d expect that it would only work in a subset of cases (like those with MECP2 duplication syndrome), though certainly this is exactly the incremental change that will eventually lead to bigger breakthroughs. Right now, and for the foreseeable future, treatment of autism has a large behavioral component. It seems difficult, though not impossible, to imagine that those behavioral interventions could be developed in an animal model, even as good a one as this.”

 

Dr. Anthony Chan, Associate Professor, Department of Human Genetics, Yerkes National Primate Research Center, Emory University (webpage): 

Expertise: developing transgenic non-human primate models of inherited genetic diseases

“A team of scientists in China reported an exciting development of a transgenic non-human primate model of MECP2 duplication syndrome that developed autism-like behaviors. Duplication of the MECP2 gene is known to produce autism like behaviors in humans. The team employed a lentiviral vector approach to randomly insert extra copies of the human MECP2 gene into the monkey genome. Unlike other model systems, non-human primates hold great promise in recapitulating a spectrum of clinical features observed in human patients as animals age and disease progresses, which is particularly important for developmental diseases such as MECP2 duplication syndrome or autism spectrum disorders.

“The excitement of this study is the development of autistic behaviors including progressive increase in anxiety and impairment in social interaction in transgenic monkeys. The demonstration of germline transmission further suggested the potential of transgenic modeling in non-human primates. Although the number of animals used this study is limited which is not uncommon in non-human primate research, being able to capture behavioral changes similar to human patients with such a small number of animals should be underscored.

“Most of the monkeys in the study carried multiple copies of the transgene inserted randomly into the genome. The correlation between gene dosage and the progressive development of clinical phenotypes could lead to new insight on pathogenic mechanism of MECP2 duplication. However, random insertion may also be the reason for variability in behavioral assessment. Overall, this study is coherent with other transgenic monkey models of human diseases. It shows that genetically engineered nonhuman primates can be created for studying brain disorders as well as advancing preclinical research and facilitating clinical translation.”

 

Declared interests (see GENeS register of interests policy):

No interests declared

 

Reference

Autism-like behaviors and germline transmission of transgenic monkeys overexpressing MeCP2‘ by Zhen Liu et al., published in Nature on Monday 25 January, 2015.

 

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