A blood test is in development to detect autism, which can lead to earlier diagnosis and treatment.
In a potentially major advance in diagnosing autism spectrum disorder, San Diego's Pediatric Bioscience is preparing to sell a blood test later this year that would detect risk of one of its most common forms.
The company's test detects antibodies in a woman’s blood that can cause what it calls “maternal autoantibody-related” autism, which the company says, based on clinical studies, represents 23 percent of all autism cases.
The test delivers a false positive response just 1.3 percent of the time, said Jan D’Alvise, the company's president and chief executive.
If the test lives up to its billing, it could significantly improve care and prevention of autism spectrum disorder, which now occurs in 1 of 68 births. The disorder is treatable with therapy to encourage social skills. But therapy works best when started as early as possible, when the brain is still young and plastic.
"About 500,000 kids are born with developmental delays each year," she said. "Pediatricians say it can take six to 12 months to be referred to a specialist for diagnosis."
A positive test in mothers of infants or young children could expedite referral for assessment, she said. Also, if given before a planned pregnancy, the test could help women decide whether they should turn to parenting alternatives such as surrogate pregnancy or adoption.
Children of those who test positive would be sent to a specialist for a final diagnosis, expediting therapy.
Pediatric Bioscience plans to start selling the test in the third quarter of this year, D'Alvise said at the Biotech Showcase conference in San Francisco, an annual meeting of biotech investors and companies held concurrently with the JP Morgan Healthcare Conference. The company is now raising funds for that launch.
The test will cost about $1,000, and the company will partially subsidize the test for the women who aren't able to pay. Insurers are expected to reimburse for the test once they're familiar with it and have received recommendations from clinicians.
The market for such a screening method could be worth $1.8 billion annually, D’Alvise said.
While the form of autism identified by the test represents less than a quarter of all cases, a positive response for a potential mother greatly increases the overall risk, D'Alvise said at the conference.
Women who have a child with a developmental delay already have a 12 percent chance of having an autistic child. But the chance rises to 64 percent chance for those who score positive on the test.
Women who already have an autistic child have an overall 17 percent risk of having another autistic child; that risk jumps to 72 percent for those who score positive.
Risk is also higher in general for women over the age of 35.
According to the U.S. Centers for Disease Control and Prevention, about 1.2 million Americans younger than 21 have autism. That’s 30 percent higher than what the CDC reported two years ago, and more than double what the agency calculated in 2002.
Behavioral tests
No test now exists that reliably links autism to biological markers, said Eric Courchesne, a top autism researcher at UC San Diego. Genetic variants have been found that correlate with autism, but these represent only a "very, very tiny subset" of all autism cases, Courchesne said.
"For some of those genes, defects are found in non-autistic individuals as well," he said. "So the search for genetic markers of autism is ongoing."
Tests for autism all look for behavioral clues, said Courchesne, who recently published research pointing to structural abnormalities in the brains of autistic children. These abnormalities were found by examining postmortem brain tissue from children with and without autism, all between the ages of 2 and 15.
But such analysis can't be performed on the living, so assessments look at behavior.
In 2010, UC San Diego autism researcher Karen Pierce co-authored a study in the Archives of General Psychiatry showing that an autism diagnosis was foreshadowed for infants as young as 14 months if they preferred seeing movies of geometric shapes to children dancing or doing yoga.
And abnormalities in eye-tracking in 2-to-6-month-old infants correlate to later autism diagnosis. Research on the correlation waspublished by Emory University researchers in November, 2013 in the journal Nature.
These tests indicate that the attention of autistic children is fixated on objects instead of other people.
Immune research
Pediatric Bioscience chief executive D'Alvise said the company started developing its test several years ago, based on studies led by UC Davis researcher Judy Van de Water, an immunologist who has long been investigating how the immune system is involved with autism.
Scientists traditionally assumed that immune activity was reduced in pregnant women to allow the mother to tolerate the developing baby. However, recent research has found that the immune system becomes hyperactive.
For example, a study by Stanford University researchers found that the immune cells of pregnant women over-react to flu viruses. The research, led by Dr. Catherine Blish, was published Sept. 22, 2014in the Proceedings of the National Academy of Sciences.
Because of this hyperactivity, the test isn't appropriate for pregnant women, D'Alvise said.
In autism, the theory is that in some women, antibodies attack certain proteins important to the fetal brain, impairing its normal development.
Van de Water and colleagues have so far identified seven antibodies involved in autism. They expect to find more as research continues.
In their most recent study, published in the journal Cerebral Cortex, the scientists tested the effect of human maternal autoantibodies on fetal mice. They found that the antibodies affect glial brain cells in the ventricular zone of the developing mouse brain. This provides a mechanism to explain development of autism, the study concluded.
Elizabeth Thomas, a scientist who studies autism and other neurological disorders at The Scripps Research Institute, commended Van de Water and colleagues as "pioneers in this provocative area of research." However, Thomas, who was sent the Cerebral Cortex study for review, said the research isn't quite at the stage where an autism spectrum disorder test should be marketed.
"While these studies are compelling to provide a pathogenic mechanism for how maternal antibodies may cause ASD symptoms, it is still not clear that the implicated proteins are the most relevant ones for ASD; hence it seems a bit premature to be marketing a diagnostic test for ASD based on these proteins," Thomas said by email.
"Antibodies often bind to many possible targets. A more convincing study would employ the use of individual antibodies purified against each of the proteins making up the diagnostic screen, and studying their effects on mouse neurodevelopment and behavior," Thomas wrote.
D'Alvise replied that she is aware of the criticism among researchers, but is confident the test will pass regulatory muster and be clinically useful. The test is now being examined for certification for use in a lab certified under CLIA standards.
"We have a team who has done this so many times, who have launched literally hundreds of clinical diagnostic tests," D'Alvise said. "We know what is required, and we all wouldn't be so dedicated and committed to this if we didn't believe that this test is going to meet all the standards with flying colors."
While more research is needed and ongoing, D'Alvise said the set of autoantibodies used in the test functions as a "very specific set of biomarkers for a major subtype of ASD."
The test will go through a large, blinded clinical validation study, which the company plans to complete this spring, D'Alvise said. The results will then be presented to CLIA. The company expects CLIA will then certify the Pediatric Bioscience testing laboratory, allowing it to market the test.
Van de Water also replied in an emailed response, stating that the research on the maternal autoantibodies extends far beyond the Cerebral Cortex article and even autism itself.
"The notion that an autoantibody can be a useful biomarker of disease risk, even when the role of those autoantibodies in disease pathogenies remains unclear, has precedence in several autoimmune disorders including those associated with SLE (anti-Ro/SSA, anti-La/SSB, anti-snRNP, and anti-Sm, and anti-double stranded DNA (anti-dsDNA))," van de Water wrote.
"While detection of autoantibodies to these nuclear antigens have been used for the diagnosis and monitoring of SLE for decades, their specific role in the pathology of this disorder are still largely unknown. This is the case for several, but not all, autoantibody associated autoimmune disordersm" Van de Water wrote.
"While it is hoped that in the future we might be able to use our knowledge regarding the identity of these autoantigens to explore possible therapeutic avenues, there is still a great deal of research to be done regarding which of the autoantibodies are most relevant to the changes in brain development."
From research to test
As one part of getting the findings from research to clinical use, Pediatric Bioscience had to calibrate how to interpret the presence or absence of the maternal antibodies to make the test reliable, with a special emphasis on reducing false positives. This is important to avoid providing false alarms.
At the same time, a positive result must predict a significant enough increase in risk to make it worthwhile.
The test was originally scheduled to launch late last year. During that time, the company changed how it performs the screening — from a complicated manual process that takes highly trained personnel to run -- to a more automated system that can scale to to the volume expected. D'Alvise said the automated system provides results as good or probably better than the original method.
“That gave us the confidence to move into full-stage development,” she added.
The company, which now has about 7 full-time employees, is preparing to expand with the introduction of the test. The company expects to have about 18 employees by the end of 2015, D'Alvise said.
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