Introduction to Autism and Leucovorin
Caroline Connor’s concerns about her son’s development began around his first birthday, when she noticed he wasn’t talking or using any words. Their pediatrician didn’t seem worried, but the speech delay persisted. At 2½, Mason was diagnosed with autism. The Connors went on a mission, searching for anything that would help. “We just started researching on our own. And that’s when my husband Joe came across Dr. Frye in a research study he was doing,” Caroline said.
Dr. Frye and Leucovorin Research
Richard Frye, a pediatric neurologist, is one of many doctors searching for treatments that can help kids with autism. He’s studying leucovorin, an inexpensive, generic drug derived from folic acid, also known as folate or vitamin B9. Leucovorin is currently prescribed to ease the side effects of cancer chemotherapy. Pregnant women are prescribed multivitamins with folic acid to prevent neural tube defects. The neural tube develops into the brain and spinal cord. Leucovorin isn’t a cure for autism, but “it could really have a substantial impact on a very good percentage of children with autism,” Frye said.
FDA Approval Process
This week, the FDA began the process of approving leucovorin as a treatment for autism, despite a lack of any large, phase 3 clinical trials. “We do have some good preliminary evidence that leucovorin helps,” Frye said. “But normally, the FDA would want to see at least a couple of large phase 3, placebo-controlled, randomized clinical trials. Right now, we only have phase 2B studies, and more research is needed to answer key questions, like how to dose it correctly, when to start, and which children will benefit most.” The theory behind the drug’s use for autism postulates that some children have a blockage in the transport of folic acid into the brain that potentially contributes to some of the neurological problems associated with the disorder. Leucovorin bypasses that blockage and can help some autistic kids improve their ability to speak. Three randomized controlled trials of leucovorin to treat autism have shown positive effects on speech.
The Science of Cerebral Folate Deficiency
Cerebral folate deficiency, or a deficiency of folate in the brain, was first described by physician-researcher Vincent Ramaekers. Ramaekers found that some kids with neurodevelopmental disorders had normal levels of folic acid in the blood, but low levels in their spinal fluid. He then teamed up with researcher Edward Quadros, who had been studying how an autoimmune disorder might lead to a blockage of folic acid transport into the brain. Ramaekers and Quadros found that autoantibodies against the folate receptor alpha (FR⍺), which transports folic acid from the blood into the brain and the placenta, might cause abnormal fetal brain development and some autism spectrum disorders. One study found that over 75% of children with autism spectrum disorder had FR⍺ autoantibodies, compared with 10%-15% of healthy kids. There is evidence of a familial or genetic predisposition for developing FR⍺ autoantibodies. While environmental and immune system dysregulation may also play a role, there’s no evidence to suggest that vaccines cause the development of FR⍺ autoantibodies.
Treatment with Leucovorin
The brain has a backup system to the FR⍺ known as the reduced folate carrier, or RFC. The RFC isn’t as efficient a transporter as the FR⍺, but it can transport leucovorin, also known as folinic acid, into the brain. Enzymes in the brain convert leucovorin into the active form of folate. Treatment with leucovorin increases brain levels of folate in kids with cerebral folate deficiency, or CFD. In one study led by Frye, one-third of such kids experienced improvement in their speech and other behavior when treated with leucovorin. Two randomized trials conducted in France and India showed similar results. A folate receptor autoantibody test (FRAT) is available to help identify which children may most likely respond to leucovorin treatment. Frye’s team has also identified new potential biomarkers, such as the soluble folate receptor protein, that could predict which children require higher doses.
Mason’s Story
Mason Connor’s first words came just three days after he started taking leucovorin at age 3, his parents say. Doctors can currently prescribe the drug only for autism off-label, which means repurposing a drug approved for one condition to treat another. “We’ve done the science, and the next step is that we want to get more funding so we can actually get it FDA-approved,” Frye said. He welcomed the FDA’s recent interest but cautioned that it “may have been a little premature,” given the gaps in knowledge and the need for physician education on how to prescribe leucovorin correctly in autism.
Challenges in Leucovorin Production and Distribution
There’s one big problem. “Leucovorin’s an old drug, and you can get it for a very low price. So nobody is going to make a lot of money on it. So there’s no reason for them to invest,” Frye said. Compounding the challenge: supply and quality vary. “Leucovorin is a generic, and different manufacturers use different additives,” Frye explained. “Some formulations children with autism don’t tolerate well.” Frye used to recommend that patients use the generic form of leucovorin manufactured by West-Ward Pharmaceuticals, a U.S. subsidiary of Hikma, but, he said, “it ran out early this year. Right now, the only reliable source is through a high-quality compounding pharmacy that knows how to make it for kids with autism.” Frye is in the process of establishing a for-profit company to manufacture the right form of leucovorin for kids with autism.
Off-Label Prescriptions and Every Cure
An estimated 20%-30% of all prescriptions in the U.S. are off-label, according to the nonprofit Every Cure. This is often done as there are more than 14,000 known human diseases with no FDA-approved drugs to treat them. Drugs like leucovorin are frequently used off-label because doctors believe that the benefits outweigh the risks. However, there is often limited awareness about these treatments, so they may go unused. David Fajgenbaum, Every Cure’s co-founder and president, said he’s “literally alive today from a repurposed drug” after he was diagnosed with a rare cancer-like disease that almost killed him. His research into his disease led to a drug meant for another condition. Every Cure uses AI to scour available medical data on diseases and treatments to uncover potential matches. Every Cure brought to light the work of Frye, Ramaekers, Quadros, and others on leucovorin in the treatment of autism.
Conclusion
Mason is now 5, and the plan is for him to start mainstream kindergarten this fall — helped toward a new path by an old medicine. While leucovorin shows promise in treating autism, more research is needed to fully understand its effects and to make it widely available to those who need it. With continued research and support, it is possible that leucovorin could become a valuable tool in the treatment of autism, helping children like Mason to communicate and thrive.
FAQs
Q: What is leucovorin and how is it used to treat autism?
A: Leucovorin is a generic drug derived from folic acid that is currently prescribed to ease the side effects of cancer chemotherapy. It has shown promise in treating autism by bypassing a blockage in the transport of folic acid into the brain, which can help improve speech and other behaviors in some children with autism.
Q: What is cerebral folate deficiency and how is it related to autism?
A: Cerebral folate deficiency is a condition in which the brain has low levels of folate, which can contribute to neurological problems associated with autism. Some children with autism have autoantibodies against the folate receptor alpha, which can cause abnormal fetal brain development and cerebral folate deficiency.
Q: How can I get leucovorin for my child with autism?
A: Currently, leucovorin can only be prescribed off-label for autism, which means that it is not specifically approved by the FDA for this use. However, some doctors may prescribe it if they believe it will be beneficial for the child. It is essential to consult with a healthcare professional to discuss the potential benefits and risks of leucovorin treatment for autism.
Q: What are the potential side effects of leucovorin treatment?
A: The side effects associated with leucovorin are generally mild. Some children may experience hyperactivity during the first few weeks of treatment, but this typically subsides within a month or two.
Q: How can I learn more about leucovorin and its potential use in treating autism?
A: You can learn more about leucovorin and its potential use in treating autism by consulting with a healthcare professional or by visiting the website of organizations such as Every Cure, which provides information and resources on repurposed drugs and their potential use in treating various diseases, including autism.
