Caroline Connor鈥檚 concerns about her son鈥檚 development began around his 1st birthday, when she noticed he wasn鈥檛 talking or using any words. Their pediatrician didn鈥檛 seem worried, but the speech delay persisted. At 2陆, Mason was .
The Connors went on a mission, searching for anything that would help.
鈥淲e just started researching on our own. And that鈥檚 when my husband Joe came across Dr. Frye in a research study he was doing,鈥 Caroline said.
Richard Frye, a pediatric neurologist, is one of many doctors searching for treatments that can help . He鈥檚 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鈥檛 a cure for autism, but 鈥渋t could really have a substantial impact on a very good percentage of children with autism,鈥 Frye said.
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.
鈥淲e do have some good preliminary evidence that leucovorin helps,鈥 Frye said. 鈥淏ut 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.鈥
The theory behind the drug鈥檚 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.
Frye cited five blinded controlled studies to date, all positive, although at different doses and in different populations. Still, he said, 鈥渢he evidence isn鈥檛 yet where it would normally be for a drug.鈥
Frye said he was 鈥渄isappointed鈥 that his group had not received funding from the National Institutes of Health鈥檚 new and that he was not consulted on the design of upcoming leucovorin trials. 鈥淚t鈥檚 strange, because I鈥檝e been leading this work for decades,鈥 he noted.
The Science of Cerebral Folate Deficiency
Cerebral folate deficiency, or a deficiency of folate in the brain, was . 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鈲), 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 , compared with 10%-15% of healthy kids. There is evidence of a for developing FR鈲 autoantibodies. While environmental and immune system dysregulation may also play a role, there鈥檚 no evidence to suggest that vaccines cause the development of FR鈲 autoantibodies.
The brain has a backup system to the FR鈲 known as the reduced folate carrier, or RFC. The RFC isn鈥檛 as efficient a transporter as the FR鈲, 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 in kids with cerebral folate deficiency, or CFD. In one study led by Frye, one-third of such kids in their speech and other behavior when treated with leucovorin. Two randomized trials conducted in France and India showed similar results. A is available to help may most likely respond to leucovorin treatment.
Frye鈥檚 team has also identified new potential biomarkers, such as the soluble folate receptor protein, that could predict which children require higher doses.
Frye noted that there are many nuances to treating CFD with leucovorin, including the addition of adjunctive treatments to optimize mitochondrial function.
The side effects associated with leucovorin are mild. Some children experience hyperactivity during the first few weeks of treatment, but that typically subsides within a month or two. A similar pattern is seen with other B vitamins.
Mason鈥檚 鈥楲ittle Bottle of Hope鈥
Mason Connor鈥檚 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.
鈥淲e鈥檝e done the science, and the next step is that we want to get more funding so we can actually get it FDA-approved,鈥 Frye said.
He welcomed the but cautioned that it 鈥渕ay have been a little premature,鈥 given the gaps in knowledge and the need for physician education on how to prescribe leucovorin correctly in autism.
There鈥檚 one big problem. 鈥淟eucovorin鈥檚 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鈥檚 no reason for them to invest,鈥 Frye said.
Compounding the challenge: supply and quality vary. 鈥淟eucovorin is a generic, and different manufacturers use different additives,鈥 Frye explained. 鈥淪ome formulations children with autism don鈥檛 tolerate well.鈥
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, 鈥渋t 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.鈥 Frye is in the process of establishing a for-profit company to manufacture the right form of leucovorin for kids with autism.
An estimated 20%-30% of all prescriptions in the U.S. are off-label, according to the nonprofit . 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.
, Every Cure鈥檚 co-founder and president, said he鈥檚 鈥渓iterally alive today from a repurposed drug鈥 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.
鈥淚t鈥檚 heartbreaking to think about drugs being on the pharmacy shelf while someone suffers from a disease,鈥 Fajgenbaum said.
Every Cure uses AI to scour available medical data on diseases and treatments to uncover potential matches. the work of Frye, Ramaekers, Quadros, and others on leucovorin in the treatment of autism.
鈥淚 think our system is just flawed and there鈥檚 this major gap where drug companies are great at developing new drugs for new diseases, and we as a system are really lousy at looking for new diseases for old drugs. That鈥檚 why we started Every Cure 鈥 to unlock these hidden cures,鈥 Fajgenbaum said.
Mason is now 5, and the plan is for him to start mainstream kindergarten this fall 鈥 helped toward a new path by an old medicine.
