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A Human (And Humane) Quest To Find Therapies For Autism Disorders

A monkey is locked in a barren, wire laboratory cage; no bedding, no toys or "environmental enrichment", nothing to look at, nothing to do. The monkey circles, paces, climbs the bars, looking for a way out because, let's face it, a life behind bars is no life at all.

A monkey is locked in a barren, wire laboratory cage; no bedding, no toys or "environmental enrichment", nothing to look at, nothing to do. The monkey circles, paces, climbs the bars, looking for a way out because, let's face it, a life behind bars is no life at all.

Another monkey in a different cage circles continually, doesn't bother to climb, just paces in circles. Unlike the first, this monkey has been genetically modified by addition of the gene "MECP2". In people, the MECP2 gene is linked to various developmental disorders classified as "autism spectrum disorders" (ASD).

So here's the question: Can artificial alterations of one gene in monkeys really cause autism? And does a monkey continually circling (displaying what is very common stereotypical behaviour for many laboratory-housed primates) be said to have "autism"?

Autism is the most common ASD and is a complex condition, affecting different people in different ways. Ironically, the rationale for manipulating one gene to create "autistic" monkeys arose from clinical observations of human patients. Over-expression of the MECP2 gene has been linked to autism in boys, and MECP2 mutations cause a specific form of ASD called Rett syndrome.

Rett syndrome is a neurodevelopmental disorder, commonly associated with autistic symptoms. Children with mutations in the MECP2 gene develop normally for around six to 18 months, then fail to meet further developmental milestones and rapidly deteriorate, losing previously learned skills such as walking, talking and gesturing. Studying children with mutations in MECP2 could help us to understand how alterations in gene expression may generate autistic symptoms, and this could lead to much-needed new treatments.

Genetically modified "animal models"

Scientists reviewing the data for the MECP2-modified monkeys recognised the stereotypical nature of the behaviour displayed and were not convinced that a monkey running around in circles could be classed as autistic. In spite of this, the primate experiments were taken further. The researchers used "Franken-science" to see if the supposed autistic behaviour was inherited. Rather than waiting four to five years for the male monkeys to reach sexual maturity, they transplanted testicular tissue from the MECP2-modified monkeys onto the backs of genetically modified mice. Within 10 months, these altered mice grew functioning monkey testicles on their backs, the monkey testicles produced monkey sperm; this sperm was then used for artificial insemination of normal female monkeys to see whether the babies would display autistic behaviour.

Benefits vs. costs

Despite decades of animal research, there is no way to reverse ASD, and an ever-increasing number of people are affected. Methods of detecting ASD have become more sensitive and our understanding of the genetic basis for ASD is improving, yet whilst early and intensive intervention may help, there is no cure. So there is a rush to generate new medicines, and it is imperative that we develop better treatment options to support people with ASD and to facilitate independence in adulthood. The question is whether animal-based science is yielding benefits that outweigh their cost - a well-established criterion for ethical science worldwide, and a legal requirement in some countries, including the UK. It seems unlikely that growing monkey organs on the backs of mice, producing modified monkeys with apparent behavioural defects (that may not even be relevant to the human disease), will provide human treatments.

A human-based approach

Leading-edge experiments carried out at the University of California San Diego (UCSD) School of Medicine by Dr Alysson Muotri and his team have provided a glimpse into the future, using a 21st century approach to study a particularly human disease. The research group took fibroblast (skin) cells from patients with Rett syndrome, and from control individuals (children without ASD). Fibroblasts are ethically obtained via small (3 mm) skin biopsies. Importantly, as mutations in MECP2 differ widely for different people, this technique allows researchers to examine a wide sample of different mutations in order to develop a universal treatment. They then used sophisticated cell culture techniques to turn these fibroblasts into induced pluripotent stem cells, the iPSC that hit the headlines regularly. Muotri's team showed that the behaviour and characteristics of cells from patients with Rett syndrome were different from the control cells, and that these changes mirrored the alterations seen in brain cells taken from autopsy tissue of patients with Rett syndrome. They confirmed the involvement of the MECP2 gene by genetic manipulation of the control cells. So, when MECP2 function in control cells was disrupted, the control cells looked and behaved like the cells from the patients with mutated MECP2.

Therapies tested in non-animal models show promise in people

An important observation of Muotri's research focused on treatment. Administration of a protein called insulin-like growth factor 1 (IGF-1) reversed the cellular changes typical of Rett syndrome; IGF-1 treatment made the cells from Rett patients look like control cells. This research finding has profound implications, and not just for children with Rett syndrome. IGF-1 does not specifically alter MECP2 expression, instead it seems to reverse the damage caused by the altered gene function. This means that IGF-1 may have more global application as a treatment for many ASD, as it is addressing the neurological defects that are the very cause of these disorders. In fact, IGF-1 has recently moved into the clinic as a treatment for a rare ASD, with a different genetic cause. The initial Phase I clinical trial indicated that IGF-1 is safe for children to take and now a larger study is planned, and is currently recruiting. This larger trial will investigate whether IGF-1 can have broader applications for other autistic spectrum disorders and will measure the impact of treatment on social impairment, language delay, and repetitive behaviour.

It is important to point out that the requirement for new medicines to be tested in animals delays the time to clinic and does not guarantee success in people. Further, with five mutant monkey babies born in 2016, one dying after just three days, and, as yet, no further insights into what MECP2 might be doing to cause the disease or how we might correct its dysfunction, it seems that reliance on animals has not accelerated our quest for a useful intervention for parents of babies born with ASD. In contrast, research using cells from the species of concern - humans - and also the very people who will benefit the most, has led to a promising clinical trial and a potential new medicine for ASD.

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