It’s been nearly a decade since my book The Forever Fix: Gene Therapy and the Boy Who Saved It, was published. The…
Headlines often trumpet the latest in gene editing, RNA drugs, or gene therapy. The less buzzy, but more classic strategy of providing a nutrient that a genetic glitch blocks, has been quietly making strides against Menkes disease, which impairs copper absorption. November is Menkes disease awareness month.
Menkes disease results from a mutation in a gene (ATP7A) on the X chromosome, so its affects boys. About 70% inherit the mutation from their mothers, who are carriers. The rest have a new mutation that arises in egg or sperm.
The healthy version of the gene encodes a protein that controls enzymes that shuttle copper from food through the lining of the small intestine into the bloodstream, and into the brain, where copper is vital for neural connectivity. The mineral is also essential for hair growth and pigmentation, which is why Menkes is also called kinky hair disease. Boys have sparse, pale, and twisty hairs.
Aside from the unusual hair, the child seems healthy until about 3 months. Then symptoms become increasingly noticeable: poor growth, developmental delay, seizures, weak muscles, and low body temperature. Many boys die before their third birthdays.
Different mutations in the gene cause milder conditions (occipital horn syndrome and ATP7A-related distal motor neuropathy). But none of the clinical variations have approved treatments.
Menkes disease was thought to affect only 1 in 34,810 newborn boys, but a recent recalculation based on genome sequencing data indicates prevalence could be as high as 1 in 8,664. That’s still pretty rare.
Daniel DeFabio, whose son Lucas lost his battle with Menkes last year, talked to me about how the family coped with COVID restrictions here and tells the family’s story in “We’re All Rare Disease Families Now“. Also see The Menkes Foundation.
Long-Term Clinical Trials
Giving boys copper is a logical treatment approach. The challenge isn’t in delivering copper – it can be injected and make its way to the bloodstream, circumventing the intestines – but in recognizing the condition soon enough after birth for supplementation to stave off symptoms. Unfortunately, newborn screening test panels don’t include Menkes. Most of these tests are still based on an analytical technique, mass spectrometry, to detect specific metabolites. But a new gene-based test that reveals Menkes disease just after (or even before) birth may soon be available.
Developing copper treatment for Menkes has taken many years, offering a compelling illustration of something I’ve written about often: the myth of the medical “breakthrough.” Most treatments, as well as preventative measures like vaccines, are typically 30 years or so in the making. “Evolution” is a more appropriate descriptor than the immediacy that “breakthrough” suggests.
The history of the development of copper histidinate (aka CuHis and CUTX-101 from drug company Cyprium Therapeutics) to treat Menkes disease unspools in a search of ClinicalTrials.gov, which returns just 5 studies. In comparison, 1,320 entries pop up for cystic fibrosis, 829 for sickle cell disease, and 2,277 for a leukemia that strikes kids.
All five entries at ClinicalTrials.gov for Menkes disease are from Stephen G. Kaler, MD, at Nationwide Children’s Hospital, and colleagues. One entry helpfully links to 15 of Dr. Kaler’s papers. Assembled chronologically, they trace the trajectory of the treatment’s development, going back to 1993. The series of cases and clinical trials indicate that the copper treatment works to varying degrees, depending on how early a boy can be treated and how severe his mutation. Many boys in the US with Menkes disease have participated in the clinical trials. Lukas was treated, but began too late to have improved, his father told me.
Mutations and Timing Matter
Development of the treatment for Menkes disease is a perfect example of the process of clinical science.
The first step was figuring out how to identify boys with Menkes during the window before symptoms appear. Because blood levels of copper at birth overlap with normal, the researchers used altered ratios of the levels of key neurochemicals in umbilical cord blood to identify affected newborns. (The test, developed in 1993, assesses levels of dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol.)
The clinical trials build toward a coming drug approval. A few highlights:
1995 Two related boys began receiving copper, one a few weeks before birth and the other at age 10 days. Their mutation changed just one amino acid in the protein, but at a position critical enough to impair transcription of the DNA to RNA – resulting in five sizes of mRNAs, with no functional protein. Despite the early treatment, both boys had severe neurological impairment, suggesting that copper replacement may only work for mild mutations. The gene is huge, so many mutations are possible. These findings led to the next step: testing copper replacement in boys with milder mutations.
1996 A boy missing a bit of DNA in a non-critical part of the gene began receiving copper injections when he was 8 days old. His head grew to a normal size, as his brain neurons became ensheathed in their essential fatty coverings. He walked at 14 months, with normal brain development. Tellingly, his half-brother and first cousin who’d inherited the same mutation but weren’t diagnosed and treated early enough, had small heads, brain degeneration, and abnormal development. So timing as well as mutation severity matter.
2008 This paper reports on 12 newborns with Menkes disease detected with neurochemical tests and treated early. Their survival at a median follow-up of 4.6 years was 92%, compared to 13% by 1.8 years for 15 boys diagnosed after symptoms began and treated later. Two of the 12 patients with mild mutations that allowed partial enzyme activity had normal neurodevelopment and brain myelination, confirming the 1996 findings.
2014 Ten boys treated early showed large improvements in both small and large movements, in personal and social behavior, and in language acquisition. Death rate by age 3 was 28.6% among boys treated early, so it isn’t perfect, but among controls, it was 50%.
Cyprium Reports 2021 Data
The latest installment in the story of conquering Menkes disease came in a poster presentation at the 2021 American Academy of Pediatrics National Conference and Exhibition on October 8.
Cyprium Therapeutic’s data are striking. Participants were born after 1999 and had severe mutations. They received the drug under the skin twice daily until a year old, and daily after that, for up to 3 years. Sixty-six boys began treatment before 4 weeks of age and 35 after 4 weeks.
Median overall survival of patients treated early was 177.1 months (just under 15 years), compared to slightly more than a year (16.1 months) for those treated after the age of 4 weeks. Still, the patients treated later lived considerably longer than 18 boys not treated at all.
The results are so promising that the company may submit a New Drug Application to FDA by year’s end.
So kudos to the researchers, the health care providers, and the families who have allowed their sons to participate in the quest to conquer Menkes disease. Hopefully soon, another rare genetic disease will bite the dust.