In a first-in-human study, supplementation with 4-hydroxybenzoic acid (4-HBA) was found to be safe and effective in a three-year-old patient with primary coenzyme Q (CoQ) deficiency. Study findings were recently published in Brain.
CoQ is a crucial molecule that works within the mitochondria to produce energy for cells. The researchers investigated 4-HBA, a precursor of CoQ, as a potential substrate enhancement treatment for individuals with CoQ deficiency. This therapeutic strategy mimics that of doxecitine and doxribtimine, a drug that helps to replenish mitochondrial DNA stores in thymidine kinase 2 deficiency (TK2d).
In a mouse model with mutations in the COQ2 gene, 4-HBA reduced perinatal mortality, cardiomyopathy, swelling and neurodevelopmental delays. In fact, mice treated daily with 4-HBA during pregnancy were indistinguishable from mice without the mutation.
When the investigators discontinued treatment during adulthood, however, the mice experienced weight loss and encephalopathy (brain dysfunction). These findings suggest that repeated administration is necessary to maintain clinical benefits.
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The authors also attempted supplementation with CoQ10, the typical treatment for primary CoQ deficiency. 4-HBA-treated mice experienced superior motor function and survival than CoQ10-treated mice.
Later, the researchers identified a child with developmental delays, including speech delays, and low muscle tone. At 3 years of age, he was diagnosed with CoQ deficiency caused by mutations in the COQ2 gene. He experienced minimal improvement with CoQ10 supplementation, which was discontinued before the trial.
After one month of oral 4-HBA treatment, his lactate levels decreased significantly, while CoQ10 levels rose. The patient’s kidney function also showed marked improvements. After six months of follow-up, his family reported no side effects.
Family members and health care professionals observed notable improvements in motor function, ability to exercise and mobility. The child’s ability to eat also improved, with him gaining two kilograms (about 4.5 pounds) over the course of four months.
In terms of cognitive changes, the patient developed an expanded vocabulary and displayed enhanced concentration and social skills.
“Our study provides robust preclinical and clinical evidence supporting the safety and efficacy of 4-HBA supplementation as a novel therapeutic strategy,” the authors concluded. “Further investigations will be critical to assess the therapeutic applicability of 4-HBA in other forms of primary CoQ deficiency caused by upstream defects in the biosynthetic pathway, and to pave the way for regulatory approval and clinical translation.”
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