A new blood test for neuro-developmental disorders
A young woman of childbearing age goes in for her annual physical exam. Her doctor suggests a blood draw to test for the presence of abnormal folate receptor autoantibodies that are implicated in subfertility, neural tube defects, cerebral folate deficiency syndrome, autism spectrum disorders, and possibly other pregnancy and developmental disorders. If the antibody is present, and she is contemplating becoming pregnant, the doctor prescribes high doses of folinic acid, a metabolically active form of folic acid or vitamin B9, sufficient to significantly reduce the risk of these serious disorders from affecting her children.
Such a scenario may not be far off, according to Edward Quadros, professor of medicine at SUNY Downstate Medical Center, who created the Folate Receptor Antibody TestTM (FRATTM) to detect folate receptor antibodies. The Research Foundation for SUNY has licensed FRATTM to Iliad Neurosciences. A life sciences company that develops products for the diagnosis and treatment of neuro-development disorders, Iliad performs the test in a CLIA-certified (Clinical Laboratory Improvement Amendment-certified) laboratory.
“The development of FRATTM could well turn out to be a seminal work that will improve the lives of many people, especially children and pregnant women,” said Boas Gonen, president and CEO of Iliad Neurosciences. “The test is essential for the diagnosis of cerebral folate deficiency, and is extremely useful in identifying patients with autism spectrum disorders, schizophrenia, and major depression who could benefit from high-dose folinic acid therapy. FRATTM is a non-invasive test when compared to lumbar puncture or spinal tap. Lumbar puncture is a painful and sometimes risky procedure needed to directly analzye level of folate in the cerebrospinal fluid. But FRATTM is a blood test for the folate receptor antibodies, which indirectly can indicate if cerebrospinal fluid is low in folate.
Gonen noted that samples already have been received from people in almost every state in the United States and from many countries in Europe, the Far East, Australia, and Latin America. “Iliad currently is engaged in educating the medical community on the utility and merits of the test, and hopes to greatly increase its utility for patients worldwide,” he said.
FRATTM is the culmination of 30 years of research on folate, the naturally occurring form of folic acid, for Quadros. All that time he has been investigating how folate deficiency leads to neural tube defects and other disorders. But it wasn’t until recently that he got an answer.
“Folic acid [an oxidized synthetic compound used to fortify food and supplements] is known to prevent neural tube defects in some women, but we noticed that most of the women who had a child with a neural tube defect were not folate deficient as measured in blood. Something else was going on,” said Quadros.
Quadros explained that he and his colleagues injected a polyclonal antibody to the folate receptor into pregnant rats. “These rats had fetuses with malformed brains and other problems,” he said. “Based on that observation we decided to recruit women with a history of neural tube defect pregnancy to see if they had an autoantibody to the folate receptor. In a small preliminary study, 70 percent of these women were positive for the folate receptor antibodies. We believe the antibody blocks folate transfer from the mother to the fetus, so the mother is folate replete but the fetus is folate deficient. It was the first evidence that an autoimmune mechanism could cause the complications of brain development and neural tube defect pregnancy.”
According to Quadros, the antibody not only causes problems for fetal development when it’s present in mothers, but it also can develop in children. “We believe that many kids who develop these neuro-developmental disorders have decreased folate transport across the blood-brain barrier because it is blocked by the antibody as it attaches to the folate receptor. The folate receptor is the primary transporter of folate to the brain.”
To do the work, the team first designed, among numerous human studies, a large double-blind placebo-controlled trial and found that 70 percent of kids with autism spectrum disorder were positive for the antibody. The researchers gave a subset of these children high doses of folinic acid and saw significant improvements in language, social interactions, concentration, learning, and other factors. “The folinic acid treatments didn’t correct all of the deficits, but it did correct some of the core deficits of autism,” said Quadros. The reason why folinic acid is the form of folate used for treatment is that it can be carried across the blood-brain barrier without the folate receptor, unlike folic acid which cannot.
Recently, the Quadros laboratory has developed a rat model to test the pathologic consequences of exposure to folate receptor antibodies. They have shown severe behavioral deficits in rat pups born to mothers exposed to these antibodies and that folinic acid can prevent these deficits. The laboratory is actively investigating genetic and other consequences of exposure to folate receptor antibodies and how to prevent these. “Folate plays a pivotal role in the structural integration and functional refinement of the developing brain, and folate receptor autoimmune processes may be a major contributor to many of the neuro-developmental disorders,” said Quadros.
In 2011, Quadros received an investment from the SUNY Technology Accelerator Fund, to further develop a clinically useful tool—FRATTM—to diagnose the risk of folate-related problems in women of childbearing age as well as in young children with developmental disorders. The commercialization of FRATTM falls within the University’s public mission to promote the use of SUNY researchers’ intellectual property for the development of novel methods and products that improve the health and well-being of the nation and the world, says David Schoenhaut, director of the Office of Technology Commercialization.
“SUNY Downstate Medical Center’s Office of Technology Commercialization was able to find a small group of entrepreneurs and investors who formed Iliad Neurosciences to commercialize and validate the test, and is very pleased that Iliad’s recently received certification under federal CLIA regulations to offer this test to doctors and their patients,” he said. “It is a rewarding example of how SUNY-Downstate partners with the private sector to develop innovations for the improvement of human health reaching beyond our local patient care facilities and academic research programs.”
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