Saturday, July 6, 2013

A new paradigm for autism therapy from cancer research

I do not have much time to read for pleasure, but before a long flight I finally managed to pick up a copy of The Emperor of All Maladies, Siddartha Mukherjee's Pulitzer-prize winning "biography of cancer". The book is masterfully written and absolutely mesmerizing, but it is not my goal to review it here, as more poignant reviews were penned 3 years ago when it was first published.

As a scientist one of the most fascinating things is to follow the process of discovery: see what physicians and scientists inferred from what they saw and how they came to often very wrong conclusions with the very best intentions, how ideas became fixed in the common knowledge and how revolutionary approaches came to be. Like the organisms and molecules it studies, medical science is constantly evolving and ways for looking at scientific problems with new eyes are always necessary.

One thing that struck me of the evolution of the thinking about cancer, is the fact that at first we did not know that the same name encompasses multiple different disorders and the common approach was to find a cure-all drug that would work on everyone. After much often devastating trial and error, we now known specific drug regimens may only work on a specific form of cancer. Cancer is in fact becoming the poster-child for personalized medicine, an approach requiring a specific understanding of the individual patient's and tumor's history and genetic makeup. The rationale is that each type of cancer and maybe each individual cancer is different and the hope is that once we figure out what makes each tumor explode in millions of proliferating cells, we may be able to design a tailored regimen to stop it.

Reading about those initial struggles on how to deal with a very heterogeneous disorder that yet often looks similar in many patients, made me thing about the changing concept of autism nowadays. The herculean genetic efforts of the past few years have determined that autism is not caused by common genetic changes, but it is more likely due to a single faulty gene in each case. The rub is that the mutated gene could be one of dozens or hundreds, and as many clinicians and parents may tell you, each affected child may need to be considered as a unique presentation of the disease. This confusion is reflected in the recent changes to diagnostic criteria listed in the latest version of the Diagnostic and Statistical Manual of Mental Disorders or DSM-5, which groups all autistic-like symptoms of different severity under the term Autism Spectrum Disorders (ASD). So, is it one big disease or hundreds of different ones that we cannot diagnose individually? Is there a miracle drug which will work on everyone in the spectrum or do we need to figure out a way to group patients with defects in similar molecular processes, or even treat everyone differently?

Some food for thought came from the recent demise of arbaclofen, an experimental drug for autistic behavior in individuals affected by Fragile X Syndrome. Fragile X Syndrome is a common cause of intellectual disability and is often associated with autistic features, but as in all forms of ASD the symptoms and the behavioral problems are greatly variable. As described in a New York Times article last month, arbaclofen was deemed a failure after it showed no affect on a phase 3 clinical trial and funding was pulled. Yet a small number of patients showed remarkable improvement in their social interactions and parents are desperate that they will now lose access to the drug. It is possible that arbaclofen may only be effective in a specific subset of cases and that other patients may need different drugs. It is also possible that the children who responded well to arbaclofen may have improved on their own or responded to anything, but we will never know if we do not test these conflicting hypotheses. If there is a "type" of autism that responds well to a specific drug, it may possible to discover more types and their treatment, as is being done for cancer.

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