Breakthrough in drug therapy for autism

28 June, 2007:

An international team, including Indian neuroscientists, has, for the first time, reversed symptoms of mental retardation and autism in mice.

The breakthrough raises hopes of drug therapy for this disorder that affects one in 500 children.

Researchers at the National Centre for Biological Sciences (NCBS) and the National Institute of Mental Health and Neuroscience (NIMHANS) in Bangalore, India, have contributed to the new finding, according to the proceedings of the National Academy of Sciences of the United States.

Scientists at the Massachusetts Institute of Technology (MIT) in the United States and Seoul National University in South Korea are part of the team.

Autism is a developmental disorder characterised by varying degrees of deficiencies in communication skills and social interactions, along with restricted, repetitive and stereotyped patterns of behaviour.

A strain of mice, genetically engineered by Nobel laureate Susumu Tonegawa and colleagues at the Massachusetts Institute of Technology, were manipulated to model ‘fragile X syndrome (FXS)’ – the leading inherited cause of mental retardation and the most common genetic cause of autism.

According to researcher Sumantra Chatterji at the National Centre for Biological Sciences, the condition, tied to a mutated gene in the X chromosome, causes mild learning disabilities to severe autism. At present there is no effective treatment for FXS and other types of autism affecting all races and ethnic groups, Chatterji said.

Chatterji said the team’s findings have identified a specific enzyme in the brain, called p21-activated kinase (PAK), as a potential target for drugs that may reverse many of the debilitating symptoms of FXS, and possibly autism, in children. The enzyme PAK affects the number, size and shape of connections between neurons in the brain.

In the brain, these connections between neurons are formed by small protrusions called ‘spines’ which are spread on branches of neurons called ‘dendrites.’ The numbers and shapes of dendritic spines are crucial for normal brain function.

FXS patients have higher numbers of dendritic spines in their brains, but each spine is longer and thinner than in normal individuals.

The team’s analysis showed that inhibition of PAK activity reverses the structural abnormality of neuronal connections seen in FXS mice.

In addition to structural problems, these abnormal connections between neurons transmit weaker electric signals in FXS mice.

Blocking PAK activity also helped restore electrical signalling between neurons in the brains of the FXS mice, Chatterji said.

The FXS mice also exhibit abnormal behavioural symptoms like hyperactivity, purposeless, repetitive movements and learning difficulties commonly seen in autistic patients.

These behavioural problems are also ameliorated in the FXS mice with reduced PAK activity. The cutting-edge genetic engineering techniques used by the collaborators at the MIT created a unique situation where PAK activity was blocked only after the debilitating symptoms of FXS had already taken hold in the mice.

“That PAK inhibition can reverse pre-existing symptoms of FXS is very good news for future design of drugs for treating fragile X in kids,” according to Chatterji.

There are known chemical compounds that inhibit the activity of PAK. These compounds or new ones targeted at PAK may greatly facilitate future development of drugs against FXS, and possibly autism as well.