A cross-sectional illustration showing a mitochondrion, a structure found in cells that oxidizes fats and sugars to produce energy in a process called cellular respiration.
Credit: Getty Images / NANOCLUSTERING / SCIENCE PHOTO LIBRARY
Young parents had already mourned the loss of two infant sons due to a rare and often fatal neurodevelopmental disorder when their 8-year-old son began displaying some of the same terrifying symptoms, including worsening paralysis. But a first-of-its-kind experimental treatment at NYU Langone Health, administered as part of a new study, led to dramatic improvement. Within two months, the boy was able to walk long distances and even run again.
This remarkable sequence of events, by a research team led by radiation oncologist Michael E. Pacold, MD, PhD, shows how the discovery of a critical metabolic pathway can lead to a potentially lifesaving disease intervention. Ultimately, the breakthrough came from asking a deceptively simple question: How do cells use oxygen?
“To me, this speaks to the power of fundamental discovery science,” Dr. Pacold says. “Quite unexpectedly, we’ve seen a benefit to a patient from our basic science discoveries within a few years of our initial publication.” , was led by postdoctoral researcher , now an assistant professor of biochemistry and molecular pharmacology at NYU Langone.
The Pacold Lab used a chemical tag to track how oxygen is used by cellular enzymes and incorporated into molecules. The technique revealed that an oxygen-dependent enzyme called HPDL drives a series of reactions that allow mitochondria, the cell’s “powerhouses,” to produce energy critical for cellular functions.
Researchers found that the HPDL enzyme first makes a metabolite called 4-HMA, which then helps create a second metabolite called 4-HB. In turn, 4-HB helps form a powerful antioxidant—and popular supplement—called coenzyme Q10, or CoQ10. “Without CoQ10, you lose about half of the efficiency of mitochondrial energy production, if not more,” Dr. Pacold says.
For years, scientists had been puzzled by variants in the gene encoding HPDL. These have been linked to rare neurodevelopmental disorders in children that cause seizures, stiffness, abnormal body movements, paralysis, and severe neurodevelopmental delay. In the most severe form of the disease, children rarely live past the age of 2. Dr. Pacold and colleagues determined the cause: HPDL deficiency interferes with the stepwise production of CoQ10, wreaking havoc on energy-dependent tissues and organs like the kidneys, liver, muscles, heart, and brain.
Although CoQ10 can be taken as a dietary supplement, the oily molecule doesn’t mix well with water in the cell, so very little goes to the inner membrane of the mitochondria, where it’s needed most. Based on their enzyme pathway discoveries, his team began investigating whether mice with a fatal HPDL deficiency could be treated with 4-HMA or 4-HB, the CoQ10 building blocks. “We thought, ‘What if, instead of giving CoQ10, we could help cells make it themselves?’” he explains.
Guangbin Shi, MD, a senior research assistant in Dr. Pacold’s lab, conducted an experiment with two HPDL-deficient, nearly immobile mouse pups. One received treatment with 4-HMA; one didn’t. Within three days, the treated mouse had regained the ability to stand and walk; the other one eventually died. Dr. Shi repeated the experiment 90 times and found that 85 percent of the treated mice survived at least one year, while the untreated ones all perished. The lab achieved the same result using 4-HB, whereas CoQ10 had no effect.
The family of the boy whose younger brothers had died from the same HPDL deficiency contacted Dr. Pacold in 2023 after hearing about his lab’s results. The boy had been diagnosed with a less severe form of the disease but was still unlikely to survive. Only months after having played soccer regularly, he had to rely almost entirely on a wheelchair by the time he arrived at NYU Langone for evaluation.
NYU Langone Health received compassionate use authorization from the U.S. Food and Drug Administration to treat the boy with 4-HB. He received his initial daily dose in December 2023 under the supervision of pediatric neurologists Claire Miller, MD, PhD, and Giulietta Riboldi, MD, PhD, who is executive director of NYU Langone’s Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders.
One month later, Dr. Pacold met the patient and his parents and learned that the boy had completed a five-mile walk around Central Park. After nearly 18 months of treatment, his symptoms continued to improve, and he was once again able to jog, run, play soccer, and ride a bicycle.
Following a recent doctor visit, the boy and his parents visited Dr. Pacold. Afterward, the boy challenged him to a race. “I raced him down the hall of the hospital, and it took some doing to keep up with him,” he recalls.
Dr. Pacold cautions that treatment with 4-HB isn’t a cure, and that a clinical trial enrolling more patients with HPDL deficiency is needed to confirm the initial results. Still, the impromptu race encapsulated the potential impact of basic science. “It was this moment of unalloyed joy seeing this child who could run, then could not run, and now was able to run again,” he says.
Disclosure: Dr. Pacold, Dr. Banh, and Dr. Shi are co-inventors on patents assigned to New York University that are related to the use of 4-HMA, 4-HB, and analogues in the diagnosis and treatment of neurodevelopmental and other diseases.
