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“It’s not a cure,” he says, “but it definitely moved the needle.”

Seaside is running two late-stage trials in adults and children with Fragile X, and a study in children with different types of autism, including autism with no identifiable cause, like Jack’s. Results of the study in which Jack participated are expected later this year.

Diagnosis and condolences

For decades scientists believed genetic diseases of brain development resulted in permanent disability. “The mindset was, ‘Damn. This is a real shame. … You are faced with a lifetime of managing the symptoms as best you can,’ ” says Mark Bear, a neuroscientist at the Massachusetts Institute of Technology and co-founder of Seaside Therapeutics.

As a result, drug treatments have focused on behavior control. The commonly prescribed drugs for autistic patients – anti-psychotics such as Risperdal and Bristol-Myers Squibb Co’s Abilify — calm tantrums and prevent patients from hurting themselves or others.

“People talk about Risperdal and Abilify as sort of chemical straitjackets,” says Dr. Paul Wang, vice president of clinical development at Seaside Therapeutics. “They control problem behaviors, but they don’t really improve the desired function of people with autism.”

The work begun by Bear more than a decade ago has helped to change the approach to autism research.

Video: Autism linked to maternal obesity

Bear had been studying how learning affects the spaces, or synapses, between nerve cells, or neurons, when he made a key discovery about Fragile X.

Neurons communicate with one another across synapses via chemicals called neurotransmitters. Some neurotransmitters stimulate brain activity, others inhibit it. In a healthy brain, the two work in balance.

With Fragile X, this process is disrupted because the gene that creates the Fragile X Mental Retardation Protein, or FMRP, is not working. Bear and his colleagues proposed that the absence of FMRP led to excessive activity of the neurotransmitter glutamate in what is called the metabotropic glutamate receptor, or mGluR, pathway, resulting in the behaviors associated with Fragile X.

Thus, they posited, drugs that inhibit glutamate signaling might treat Fragile X and related disorders. Subsequent experiments showed that reducing the activity of glutamate alleviates Fragile X symptoms in both young and adult animals. “What these studies have shown is we can really get substantial benefit by correcting altered signaling,” says Bear, who also serves as a scientific adviser to Seaside Therapeutics.

When Bear first presented the idea that Fragile X could be corrected at a 1992 conference, many experts were skeptical. Now it is the prevailing theory behind treatments for Fragile X and is seen as a key to unlocking autism and other brain disorders.

“Many of the genes related to autism are right in the same pathway that has been implicated and worked out in Fragile X,” says Dr. Edwin Cook of the Autism Resource Center at Rush University Medical Center in Chicago, which is participating in the Seaside Therapeutics trials. “I don’t expect any medication to help everyone, but I think we have a good shot here.”

Seaside’s arbaclofen works by reducing the amount of glutamate available in the synapse. The experimental drug Novartis is testing works by a different mechanism; it blocks glutamate receptors on the surface of the neuron.

Novartis’s trial of its drug for Fragile X in 30 adults failed to show statistical significance. But in seven patients with the most severe form of Fragile X – those with a full mutation of the FMR1 gene – the drug showed significant reductions in hyperactivity and inappropriate speech. Novartis is now running a larger study in Fragile X, and it will test the drug for four months instead of one.

Roche also has a Fragile X drug that blocks glutamate receptors. It, too, is conducting advanced clinical trials in adults and adolescents with Fragile X.

Roche, along with advocacy group Autism Speaks and King’s College London, in March announced one of the largest-ever academic-industry research projects to find new ways to develop drugs for autism. The $39 million effort includes contributions from Roche, Eli Lilly Co, Servier, JJ, Pfizer Inc and Vifor Pharma.

“The field is coming of age,” says Luca Santarelli, global head of Roche Neurosciences.

Jim Young
 / 
Reuters

Grim prognosis

Holly Roos is a carrier of the genetic mutation that causes Fragile X, and both her son Parker, 12, and her daughter Allison, 9, have varying degrees of Fragile X.

Parker hit all the early developmental milestones – rolling over, sitting up, crawling and walking – but his fine motor and language skills stalled.

Holly, who worked in a child-care center near her home in Canton, Illinois, wasn’t reassured when doctors told her not to worry. Then, Holly’s mother, a nurse, attended a genetics conference in Chicago where she learned about Fragile X, and the pieces of the puzzle fell into place.

Tests showed that Parker had a full mutation in the FMR1 gene that causes Fragile X, meaning the gene was completely shut down and he was very likely to have both intellectual disability and autism.

A geneticist gave Holly the grim prognosis. Parker would live in an institution. He would never be toilet-trained. He would never go to school. He would never be independent. (His sister, like many females with Fragile X, is highly functional and shows scant impairment.)

Undaunted, Holly enrolled Parker, then 10, in one of Seaside’s trials of arbaclofen for Fragile X patients. At the time, Parker could say only a few words. Instead of talking, he screamed. “He had a happy scream, and a sad scream, and an ‘I want that’ scream,” Holly says.

School was an exercise in frustration. “If he had a rough day, he would lunge at me and bite and not let go. I had huge welts and really bad bruises on my legs and arms,” Holly recalls.

Dr. Elizabeth Berry-Kravis, director of the Fragile X clinic at Rush University Medical Center, has been studying the disease for more than two decades. Parker, she says, “was a mess. He had tantrums. … He was aggressive. He tried to knock you away.”

In Parker’s trial, 63 patients received either a placebo or arbaclofen for one month, and then they switched.

At first, nothing. Then, about two weeks after Parker switched drugs, he knocked a glass off the kitchen table. As Holly turned to pick up the shards, she heard her son say, “I am sorry, Mom. I love you.”

It was the first time he had uttered those words, and they came out in complete sentences. “I waited 10 years to hear him say, ‘I love you, Mom,’ ” Holly says.

Jim Young
 / 
Reuters

Other families had similar breakthroughs, says Dr. Randall Carpenter, Seaside’s president and chief executive officer.

Some noticed their children would hang out in the kitchen longer after they came home from school instead of holing up in their bedrooms. Others made new friends outside their special education groups for the first time. Teachers who knew nothing of the trial reported that children were more engaged in school.

Evidence behind autism drugs may be biased

But other test subjects showed only modest benefits or none at all, and the study failed to show a statistically significant effect. Berry-Kravis says the sample size was too small to demonstrate a benefit. She and others involved in the study also say it erred in choosing changes in irritability as its main goal. They say future trials will focus on the social withdrawal problems researchers are targeting with the new drugs.

Researchers say that given baclofen’s record for safety as a treatment for cerebral palsy, Seaside’s version of the drug, arbaclofen, may have a better chance of winning U.S. regulatory approval than it would if it were an entirely new compound.

Bear thinks it might be five years before any of the current drugs being tested are approved to treat Fragile X and other forms of autism. Berry-Kravis estimates 2014 at the earliest.

Until then, Jack, Parker and others helped by the medicine will be able to continue taking it through extension studies that will gather data on the long-term effects of arbaclofen.

Not a cure

In the tight-knit autism and Fragile X communities, few expect a cure, but many hope the drugs under study will give patients a chance to lead more independent lives. Stories like those of the Balters and the Rooses feed the optimism.

Neil Balter recently took Jack to a basketball game. Jack watched the players and cheered his team on — instead of sitting with his headphones on, playing video games, as he used to do.

Neil says he knows Jack is smart, but he wants more for his son: “I want him to have friends and have a life — to be socially accepted, to be able to get married. That is where I believe some of the benefit of arbaclofen comes in.”

For Parker Roos, who has been on the drug for two years, the differences are even greater. He’s now active in sports and is doing better in school.

Jim Young
 / 
Reuters

Before, a trip to the park could set off violent tantrums. Recently he attended a birthday party — at a noisy game arcade — and for the first time, Holly didn’t tag along. (She waited in the parking lot, just in case.)

When his Special Olympics basketball team made it to the state tournament in Normal, Illinois, 90 minutes from home, Parker stayed in a hotel with the rest of the team, one of the many things Holly never imagined would be possible.

Holly used to wear long-sleeve shirts year-round to conceal the bruises she got from tending to Parker. Now, with no bruises to hide, she wears T-shirts and shorts. On her left shoulder, Holly got a tattoo of a green X with the word “Fragile” written in black.

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