In 1962, a pediatric neurology resident at Columbia's Neurological Institute and his colleagues in the College of Physicians and Surgeons published a detailed paper in Pediatrics describing a new syndrome of neurodegeneration in male infants.
The resident, John Menkes, MD, had seen the index case a few years earlier at Babies Hospital (now Morgan Stanley Children's Hospital at NewYork-Presbyterian/Columbia University Irving Medical Center). The boy had met early developmental milestones such as head control and smiling by six weeks of age. But then the infant abruptly regressed. He lost weight and muscle control and soon developed frequent seizures. Nothing Menkes did seemed to help, and the child died at 18 months of age.
"Without treatment, there's an inexorable downward spiral and death often occurs by two years of age. It's obviously very rough for parents."
After examining the records of four other male infants from the same New York City family who had come to Babies Hospital with similar symptoms, Menkes deduced that the condition was an X-linked recessive genetic disorder. A decade later, the cause was identified as copper deficiency-a discovery that revealed the human brain's critical need for this trace metal. Further study would also reveal the rarity of the disease, which affects about 1 in 35,000 live male births.
"It's a tragic illness," says Stephen G. Kaler, MD, recently recruited professor of pediatrics in the Vagelos College of Physicians and Surgeons who directs the Columbia Menkes Disease Clinic. "Affected infants who are born healthy become ill within weeks, with seizures, failure to thrive, and developmental delays. Without treatment, there's an inexorable downward spiral and death often occurs by two years of age. It's obviously very rough for parents."
In the late 1980s, Kaler was a postdoc in an NIH laboratory studying human copper metabolism when he first encountered Menkes disease, as it had come to be called.
"There were several inherited disorders of copper metabolism known at that time," Kaler says. "Menkes disease was the one that seemed to have the greatest need of attention from both a basic science and treatment perspective, for which reason I was drawn to it."
Three decades on, therapies developed through Kaler's research may soon change the outlook for children born with Menkes. One, a drug that dramatically increases survival in Menkes patients, called copper histidinate (CuHis), is currently under review for new drug approval by the FDA. And a viral gene therapy developed by Kaler's laboratory, combined with CuHis, may be able to provide children with even greater benefits-and possibly long-term futures.
A first start with copper injections
Kaler's first attempt in the early 1990s at treating Menkes began with copper supplementation. A team in Canada had experimented with giving two children with Menkes disease CuHis injections to boost copper levels, and Kaler initiated a protocol at the NIH Clinical Center.
"It was a unique opportunity, since at NIH, I could treat patients from all over the country, from all over the world with this rare illness and formally evaluate its effectiveness in clinical trials."
Stephen Kaler
The early results were mixed, Kaler says. He learned that children with milder variants in the Menkes copper transport gene responded better to copper supplementation, as did children who were treated soon after birth.
Longer experience with more patients identified distinctive benefits in survival and clinical outcomes even with severe loss-of-function variants using a CuHis formulation produced at NIH and later by Cyprium Therapeutics and Sentynl Therapeutics, biopharmaceutical partners.
Among patients treated soon after birth, median survival jumped to 15 years; some participants even went to college, joined the workforce, and lead near-normal lives. Children treated later, who had already developed symptoms, also showed a survival benefit, living on average to five years of age.
"The CuHis gave parents more time with their children, and I know they deeply appreciated that," Kaler says. "But it seemed that to treat the illness more completely, we also needed a gene replacement strategy."
Injections introduce copper into the bloodstream, Kaler explains, but because mistakes in the Menkes gene impair the transport of copper, many cells including the brain's neurons do not get enough of the element.
A gene therapy plus copper supplementation solves both issues.
Gene therapy success in animal studies
Before joining Columbia in August 2024, Kaler left the NIH to work with viral gene therapy pioneers at Nationwide Children's Hospital and Ohio State University in Columbus, Ohio to create a Menkes gene therapy. The therapy, injected into the bloodstream, delivers a functional copper transporter gene to the brain.
The first preclinical tests of Kaler's latest design were published in August 2025 in Science Advances and show remarkable results when paired with CuHis injections: a single dose of the gene therapy reaches the brain and prevents the disease in nearly 100% of mice with a defect in the Menkes gene.
"The hope is that together with advances in newborn screening to enable early detection, treatment of Menkes disease with CuHis plus gene therapy will alter the natural history of this condition."
"We need to do additional animal testing to confirm the safety of this gene therapy so it can be used in human subjects, and I think we're probably a year or two away from beginning a clinical trial of the combination treatment," Kaler says. The National Institute of Neurological Disorders and Stroke (NINDS) is funding this work through their Ultra-rare Gene-based Therapy (URGenT) program. (The original description of the illness by John Menkes was also supported by grants from this organization, then called the National Institute for Neurological Diseases and Blindness.)
"The hope is that together with advances in newborn screening to enable early detection, treatment of Menkes disease with CuHis plus gene therapy will alter the natural history of this condition," Kaler says. "It would close a loop in a story for which NewYork Presbyterian/Columbia University Irving Medical Center and NINDS have been so important."
"It's been said of some endeavors, that there is no magic bullet and that progress must be measured in decades. The loss of a young child is one of life's greatest tragedies, and the recent advances and potential FDA approvals of these treatments are satisfying. There's more work to do, of course, but at least now we have rational path forward and can envision a day when the lives of children and their parents are no longer darkened by this difficult illness."
