Coenzyme Q10 Precursors Reverse Motor Decline in a Young Patient

While mitochondria may be the powerhouses of the cell, coenzyme Q10 (CoQ10) is the engineer that keeps mitochondria going. Nestled in the mitochondrial membrane, CoQ10 shuttles electrons through the electron transport chain to help mitochondria generate energy for the cell. It also acts as an antioxidant to control reactive oxygen species that can damage cell membranes.¹

“You need CoQ10 for a lot of things, and if you can't make CoQ10, then your mitochondria go down,” said Michael Pacold, a radiation oncologist at New York University Langone Health.

People with mutations in genes involved in synthesizing CoQ10—called primary CoQ10 deficiencies—typically show signs of disease from soon after birth to early childhood. These include kidney disease, cardiomyopathy, and neurological symptoms like seizures, muscle stiffness and weakness, and encephalopathy. Although rare and ranging in severity, these mitochondrial diseases can be lethal. While CoQ10 supplements can improve some aspects of these diseases, they have not been effective in treating the neurological symptoms, likely because CoQ10 has difficulty crossing the blood-brain barrier to get into the brain.¹

“The question, once these patients were discovered was, ‘Well, maybe instead of giving CoQ10, we could help these cells make it themselves,’” Pacold said.

Today, in a study published in Nature, Pacold and his team showed that providing CoQ10 precursor molecules to a mouse model of neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA) improved their neurological symptoms. The researchers also treated an eight-year-old boy who had this same condition, and the precursor molecule halted the progression of his disease and restored his ability to run and play. The findings position these molecules as potential treatments for primary CoQ10 deficiencies and other diseases that result from low levels of CoQ10.²

“It’s an interesting paper. I think it's brought the idea of treatments back into the fore,” said Iain Hargreaves, a mitochondrial disease researcher at University College London who was not associated with the study. “It's difficult to treat patients with mitochondrial disease, so this is something interesting.”

Four years ago, Pacold and his team discovered that the enzyme 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes the small molecule 4-hydroxymandelate (4-HMA), which then leads to the production of 4-hydroxybenzoate (4-HB) and eventually CoQ10.³ Pacold and his team wanted to see what happed if they treated mice that lacked the HPDL enzyme (HPDL^-/- mice) with these CoQ10 precursors.

Mice without HPDL typically die within 15 days after birth, but when Guangbin Shi, one of the co-lead authors of the study, added 4-HMA or 4-HB to their drinking water from three to 30 days post birth, the mice lived for 18 months or more. This is the typical lifespan for a healthy mouse.

“The first animal he did this in—48 hours after he started treating it—was standing up, and honestly, we didn't believe it, and he repeated it probably 90 more times. He rescued 90 of these animals,” said Pacold. “Over 85 percent of them make it to a year or more. It's about as clear a survival benefit as I've ever seen in any mouse study.”

To see whether 4-HMA and 4-HB were getting into the brain and synthesizing CoQ10 there, the team allowed the HPDL^-/- mice to drink 4-HMA and 4-HB made up of carbon-13 isotopes. They saw that the precursors led to increased levels of CoQ9 (a version of CoQ10 that’s more common than CoQ10 in mice) and CoQ10 in the mice’s brains; however, the levels of CoQ9 and CoQ10 were lower than those in mice that had one or both copies of the gene encoding HPDL. The team also saw that treating HPDL^-/- mice with 4-HMA helped the cerebellum mature, restored function of the Purkinje cells—neurons important for movement, and improved the animals’ motor functions.

“It was about this time that we were referred a patient with HPDL deficiency,” Pacold said.

At around eight years of age this boy started becoming slightly off balance when he was playing soccer. About a month later, his mother noticed that he had developed involuntary muscle contractions called clonus in his ankles. Having seen this same symptom in her two other children who had previously passed away in infancy, she brought her son to the emergency room. After sequencing the patient, clinicians found that he had the same mutations in both copies of his HPDL gene as one of his siblings who had received genetic testing and been diagnosed with NEDSWMA. Doctors started him on CoQ10 treatment.

“He continued to deteriorate. He, basically by the time he came to us, wasn't walking more than 10 to 30 meters before he stopped, would stumble, and fall, or he would become tired and need to sit down,” said Pacold. “He was progressing even through a relatively high dose of coenzyme Q.”

Because of the patient’s rapid deterioration, Pacold and his colleagues proposed treating him with 4-HB. In addition to being a precursor to CoQ10, 4-HB is a metabolite of the class of molecules called parabens, which have been well-studied for their use as preservatives. Due to their positive toxicology and safety data, the Food and Drug Administration (FDA) considers parabens to be Generally Recognized as Safe compounds.

The FDA quickly approved the researchers’ treatment plan as did New York University’s institutional review board. With the parents’ and patient’s informed consent, the team treated the patient with 4-HB in water every day. After 250 days on the treatment, he showed decreased limb spasticity, a small improvement in hand movement, improved endurance and balance, and fewer falls. His doctors stopped administering CoQ10 after several months and only treated him with 4-HB moving forward.

“The patient has actually been treated with this now for over a year,” said Pacold. “He's driving a go kart. He's jogging. He's running. He can step sideways to catch a ball. He's riding a bicycle. I mean, he's basically gone from being able to walk 10 to 20 meters to basically back to having good strength and endurance—again, not a complete rescue, but a substantial improvement.”

Hargreaves was impressed by the study, but he would have liked to see “some biochemical markers to accompany the clinical benefits,” he said. “Look at some levels, 4-hydroxybenzoate or control levels even, to see whether it is taken up and metabolized into CoQ10.” To measure CoQ10 levels in the brain, researchers can use the cerebral spinal fluid (CSF) as a surrogate, but taking a CSF sample is quite an invasive procedure. As an alternative, Hargreaves said that the research team could have considered measuring CoQ10 levels in the blood before and after 4-HB treatment.

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He also noted that 4-HB didn’t completely restore the patient to normal motor function, but he said that this may be a consequence of the timing of the patient’s treatment.

“Anything with mitochondrial disease or coenzyme Q10 deficiencies, you've got to treat them very early because otherwise the damage is done. It's a window of opportunity,” said Hargreaves. “The patient's had the disease for a while. Maybe it’s sometimes irreversible. You can't always restore to full function.”

Pacold agreed, adding, “The data from the mice and the data from the patient don't suggest that this is a complete rescue. There's a lot of work that we have to do to figure out how to make this better.”

For now, the researchers’ next step is to see if this therapy could help patients with this ultra-rare disease and those with other CoQ10 deficiencies. Pacold and his team plan to begin a clinical trial testing 4-HB in these populations to see if they can have something to offer kids with these rare and often severe conditions.

“We’re grateful we took that chance,” one of the child’s family members wrote in an email. “Working with the researchers has been both humbling and empowering. Their transparency, patience, and compassion made a world of difference in navigating something so unknown. Choosing to try an experimental treatment wasn’t easy, but the support we received gave us confidence. It felt like a leap of faith—but one taken with a safety net.”

For Pacold, he is amazed that a discovery made by his team of basic biologists was able to help a patient and improve his life.

“It's the dream that has come to life—that you find something fundamental and then deploy it in a patient,” said Pacold. “I'm very, very grateful that we've had the chance to live that dream.”