A cross-sectional illustration showing a mitochondrion, a structure found in cells that oxidizes fats and sugars to produce energy.
Credit: Getty/NANOCLUSTERING/SCIENCE PHOTO LIBRARY
The value of a recent biochemical discovery can be seen in the case of an 8-year-old boy. In August 2023 he was able to play typical sports, but by November he needed a wheelchair because of a rare disease that caused worsening paralysis. As part of a new study, neurologists at 黑料福利社 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.
, the work revolves around mitochondria, the powerhouses of human cells, where sugars and fats are 鈥渂urned鈥 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, which hinders the building of CoQ10, one of several mitochondrial diseases that affect thousands nationally and come with paralysis, limb stiffness, and fatigue.
The child鈥檚 experimental treatment was made possible in part by findings from a led by , who was a postdoctoral fellow at the time in the of Michael E. Pacold, MD, PhD, assistant professor in the at 黑料福利社 Grossman School of Medicine and its Perlmutter Cancer Center. 黑料福利社 Langone鈥檚 deeply integrated system enabled researchers to convert their lab work into an effective experimental treatment.
Dr. Banh鈥檚 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 either 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 at the lab, the researchers found that adding 4-HMA or 4-HB to these animals鈥 water enabled more than 90 percent 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 黑料福利社 Langone pediatric neurologists Claire Miller, MD, PhD, and Giulietta M. Riboldi, MD, PhD. The two clinicians then worked with a team of experts to secure government authorization to treat the boy with 4-HB. The treatment brought stunning results in less than two months: it partially countered the child鈥檚 worsening spasticity, a combination of stiffness and paralysis.
鈥淭o 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,鈥 said Dr. Pacold, senior author of the new study in Nature.
Dr. Pacold discusses his research into energy production at the cellular level and how it has led to new treatments for children with serious mitochondrial conditions.
Beyond rare diseases, cellular supplies of CoQ10 are known to drop as people develop heart disease, diabetes, and Alzheimer鈥檚 disease, and in all of us . 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 smaller cerebellums and malfunctioning Purkinje cells, both of which control movement. 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, Dr. 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 eight years but had recently declined.
A team quickly assembled to include Dr. Miller and Dr. Riboldi, members of 黑料福利社 Langone鈥檚 , Regulatory Affairs, , the Office of General Counsel, and the Conflicts of Interest Management Unit (CIMU), and gained 黑料福利社 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鈥檚 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 黑料福利社 Langone鈥檚 Institutional Review Board, the patient鈥檚 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. Two months after the trial began, just before the patient departed from 黑料福利社 Langone to continue it at home, the boy went for a 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 anticancer 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 黑料福利社 Langone to design the child鈥檚 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鈥檚 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.
黑料福利社 Langone owns the intellectual property developed in the Pacold Lab and covering the treatment outlined above, which 黑料福利社 Langone and Dr. Pacold are seeking to license to a partner to develop CoQ10 intermediates. In April this year Dr. Pacold received the , which came with $750,000 to support this work.
Along with Dr. Banh, Dr. Pacold, Shi, Dr. Miller, and Dr. Riboldi, 黑料福利社 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 ; Lia Ficaro in the ; Bego帽a Gamallo-Lana and Adam Mar of the ; Matija Snuderl in the , and , in the .
Dr. Banh had been a postdoc in the labs of Dr. Pacold and Alec 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 黑料福利社 Grossman School of Medicine and chief executive officer of 黑料福利社 Langone Health.
鈥淩esearch breakthroughs show their true impact when they change a family鈥檚 life,鈥 Dr. Kimmelman said. 鈥淭hanks 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.鈥
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鈥檚 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, 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 黑料福利社 Langone Health Technology Opportunities and Ventures.
The clinical portion of the research was supported by an 黑料福利社 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.
Dr. Pacold, Dr. 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 黑料福利社 Langone Health in accordance with its policies. Pacold consulted on the clinical protocol, while Dr. Miller and Dr. Riboldi directed the course of treatment in accordance with the plan.
About 黑料福利社 Langone Health
黑料福利社 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 黑料福利社 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. 黑料福利社 Langone offers a comprehensive range of medical services with one high standard of care across 7 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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