Experimental compound offers potential treatment for rare, often fatal childhood disease

The value of a recent biochemical discovery can be seen in the case of an 8-year-old boy, who was playing typical sports in August 2023, but by November needed a wheelchair because of a rare disease that caused worsening paralysis. As part of a new study, neurologists at NYU Langone Health treated the boy with an experimental compound that partially reversed his rapid decline. Two months after beginning treatment, he was able to walk long distances again and even run.

Published online July 9 in the journal Nature, the work revolves around mitochondria, the “powerhouses” of human cells where sugars and fats are “burned” to produce energy. This energy production requires coenzyme Q10 (CoQ10), which is made by human cells. The boy described in the paper was born with a potentially fatal condition called HPDL deficiency that hinders the building of CoQ10, one of several mitochondrial diseases that affect thousands nationally and come with paralysis, limb stiffness, and fatigue.  

The child’s experimental treatment was made possible in part by a 2021 study led by Robert Banh, PhD, who was a postdoctoral fellow at the time in the lab of Michael E. Pacold, MD, PhD, assistant professor in the Department of Radiation Oncology at NYU Grossman School of Medicine and its Perlmutter Cancer Center. NYU Langone Health’s deeply integrated system enabled researchers to convert their lab work into an effective, experimental treatment.

Banh’s original work revealed that CoQ10 building in mitochondria starts when HPDL (the enzyme hydroxyphenylpyruvate dioxygenase-like) turns a compound called 4-hydroxymandelate (4-HMA) into another called 4-hydroxybenzoate (4-HB). Cells then use 4-HB to build a part of CoQ10 necessary for energy production.

Based on this discovery, the Pacold lab was able to show that both 4-HMA or 4-HB can be used to restore CoQ10 synthesis and counter related brain damage in mice engineered to lack HPDL. Led by Guangbin Shi, a senior research assistant in Pacold’s lab, the researchers found that adding 4-HMA or 4-HB to these animals’ water enabled more than 90% of them to move near normally and live to adulthood, instead of becoming paralyzed and dying.

When the researchers were approached by the parents of the fast-declining child with HPDL deficiency, they shared their evidence with NYU Langone pediatric neurologists Claire Miller, MD, PhD, and Giulietta Riboldi, MD, PhD. The two clinicians then worked with a team of experts to secure government authorization to treat the boy with 4-HB. In a stunning result, the treatment partially countered the child’s worsening spasticity, a combination of stiffness and paralysis, in less than two months.

“To our knowledge, this is the first demonstration that neurological symptoms of a primary CoQ10 deficiency can be stabilized or improved by supplying, not CoQ10 itself, but instead its smaller, more easily processed precursors, which cells then use to build more of the coenzyme,” said Pacold, senior author of the new study in Nature.

Beyond rare diseases, cellular supplies of CoQ10 are known to drop as people develop heart disease, diabetes, and Alzheimer’s disease, and in all of us as we age. For these reasons, the industry supplying CoQ10 as a dietary supplement is expected to represent a billion-dollar market within a decade. The problem, say the current study authors, is that, even at high doses, less than 5 percent of ingested CoQ10 makes it into the body because of its structure and size. This may explain why CoQ10 has failed to reverse the neurological symptoms of HPDL/CoQ10 deficiencies, the researchers say.

Recovery Window
For the current study, the Pacold lab acquired mice engineered to lack HPDL function, which were known to quickly become paralyzed. The team also found that these mice had smaller-than-normal mitochondria, as well as a smaller cerebellum and malfunctioning Purkinje cells, both of which control movement. Remarkably, replacement therapy with 4-HMA partially reversed the abnormalities by encouraging the building of the mouse version of CoQ10.

Then in 2023, with the mouse results in hand, Pacold met the parents, both of whom had genetic mutations that sabotaged HPDL function and caused two of their children to die in infancy. Their other child had thrived for 8 years but had recently declined.

A team quickly assembled to include Drs. Miller and Riboldi, members of NYU Langone’s Office of Science & Research, Regulatory Affairs, Technology Opportunities & Ventures, the Office of General Counsel, and the Conflicts of Interest Management Unit (CIMU), and gained NYU Langone approval under its policies to clinically test 4-HB. The team next gained approval from the U.S. Federal Drug Administration for the boy’s experimental treatment under a process called expanded access. It enables physicians caring for a patient with a life-threatening disease to use an experimental treatment when no other options are available. With subsequent approval from NYU Langone’s Institutional Review Board, the patient’s treatment started in December 2023.

Treated daily with the experimental compound dissolved in water, the patient saw improved balance and endurance over the following weeks. Just before the patient departed from NYU Langone two months into the trial (to continue it at home), Miller says, the boy went for one-and-a-half mile walk with his family in Central Park. The recovery, however, was partial, with some spasticity and gait issues remaining.

The discovery of the experimental treatment was serendipitous, occurring while the Pacold Lab was investigating the anti-cancer potential of targeting CoQ10 production. During that test, the team happened to discover that the CoQ10 precursors caused recovery from neurodegenerative processes in one of its animal models. This ultimately led to an effort across NYU Langone to design the child’s treatment.  

Further, children with HPDL deficiencies are known to have a range of disease severity depending on their specific versions of key variant genes, from no function (fatal) to levels of partial function. The clinical and research teams theorize that the treated child still had some HPDL function and so was able to develop normally until a certain stage. The team’s mouse data suggest that there is a time window in neural development during which the effects of HPDL deficiency will be most reversible with CoQ10 precursor treatment, and after which treatment will have little effect. Identifying this window, along with the most effective dose, in larger studies will be the focus of the next round of research.  

NYU Langone owns the intellectual property developed in the Pacold lab and covering the treatment outlined above, which NYU Langone and Dr. Pacold are seeking to license to a partner to develop CoQ10 intermediates. Dr. Pacold in April received the Pershing Square Foundation’s “MIND” Prize , which came with $750,000 to support this work.

Along with Pacold, Banh, Shi, Riboldi, and Miller, NYU Langone study authors included Sota Kuno, Quentin Spillier, Zixuan Wang, and Drew Jones from the Department of Radiation Oncology, Megan Korn and Wyatt Tran from the Department of Biochemistry, Lia Ficaro in the Metabolomics Core Research Laboratory, Begoña Gamallo-Lana and Adam Mar of the Rodent Behavioral Laboratory, Matija Snuderl in the Department of Pathology, and Soomin Song in the IonLab. Banh had been a post-doc in the labs of Dr. Pacold, and of  Alec C. Kimmelman, MD, PhD, director of the Perlmutter Cancer Center, before joining the faculty as an assistant professor in the Department of Biochemistry and Molecular Pharmacology. Dr. Kimmelman was recently named Dean of the NYU Grossman School of Medicine and chief executive officer of NYU Langone Health.

“Research breakthroughs show their true impact when they change a family’s life,” Dr. Kimmelman said. “Thanks to an extraordinary team working across our integrated system, we were able to safely and effectively get this treatment from a bench in the lab to a patient in need.”

Authors at other institutions were Alejandro Rey Hipolito, Tao Lin, and Roy Sillitoe in the departments of Pathology and Immunology at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital; as well as Salsabiel El Nagar and Alexandra Joyner in the Developmental Biology Program at Memorial Sloan Kettering Cancer Center.

The research was supported by National Institutes of Health grants NIGMS R35 MIRA 1R35GM147119, and NCI R37CA289040, Perlmutter Cancer Center grant P30CA016087, a Damon Runyon-Rachleff Innovation Award, and Dale Frey Breakthrough awards DRR 63-20 and DRG-50-22, Tara Miller Melanoma Foundation / MRA Young Investigator Award 668365, and American Cancer Society Research Scholar Award RSG-21-115-01-MM. Additional funding came from the Harry J. Lloyd Charitable Trust, an Irma T. Hirschl Career Scientist Award, a Concern Foundation Conquer Cancer Now Grant, and from NYU Langone Health Technology Opportunities and Ventures.

The clinical portion of the research was supported by an NYU CTSA grant (includes UL1 TR001445, KL2 TR001446, and TL1 TR001447) and by funding provided through a Pershing Square-Sohn Cancer Prize from the Pershing Square Foundation.

Pacold, Banh, Shi, and Spillier are co-inventors on patents related to the use of 4-HMA, 4-HB, and analogues in the diagnosis and treatment of neurodevelopmental and other diseases assigned to New York University. The treatment was conducted and supervised by Miller and Riboldi under an institutional conflict-of-interest management plan implemented by NYU Langone Health in accordance with its policies. Pacold consulted on the clinical protocol, while Miller and Riboldi directed the course of treatment in accordance with the plan.

About NYU Langone Health
NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 115 comprehensive academic medical centers across the nation for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

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