The cancer drug elesclomol holds promise for treating copper deficiencies in Menkes disease

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A Texas A&M AgriLife Research team has good news for patients with copper-deficiency disorders, especially young children diagnosed with Menkes disease.

A team led by James Sacchettini, Ph.D. professor and Welch Chair of Science, and Vishal Gohil, Ph.D., associate professor, both from the Department of Biochemistry and Biophysics at Texas A&M University, published a paper in Science outlining their latest discoveries of how using the cancer drug elesclomol holds promise for treating copper deficiencies in Menkes disease.

“With all biology connected, it’s great to see this innovative research from the agriculture and life sciences departments making a significant connection to an area of human health,” said Patrick J. Stover, Ph.D., vice chancellor of Texas A&M AgriLife, dean of the College of Agriculture and Life Sciences and director of AgriLife Research.

Menkes disease

Menkes is a rare genetic disorder occurring in about 1 in every 50,000-300,000 births. Young children with the disorder typically die within three years of life due to a genetic mutation that limits their body’s ability to absorb and utilize copper from their diet.

The copper deficiency leads to severe brain damage and neuromuscular deficits.

“Experimental treatments have not been effective at overcoming the most severe symptoms of the disease or early mortality,” Sacchettini said.

“Our current work documenting the efficacy of elesclomol in a mouse model of Menkes disease takes us one step closer to the clinical trials,” Gohil said.

Copper deficiency

Normally, copper is acquired through diet from foods such as fish, organ meats, nuts and beans, said Liam Guthrie, a doctoral candidate in Sacchettini’s lab and lead author of the paper. He explained that dietary copper is normally absorbed in the intestines, then exported to the liver for distribution throughout the body.

In Menkes disease, that process is disrupted. The copper absorbed by intestinal cells must be exported into the blood by a copper transport protein. If that protein is not functioning well, due to genetic mutations, the copper can’t be distributed to various parts of the body. The brain, heart and other tissues thus become copper deficient.

And, when copper is deficient in these tissues, certain enzymes fail to activate, Gohil explained. One such enzyme is mitochondrial cytochrome oxidase complex, which is required for energy production.

“Mitochondrial cytochrome oxidase is an enzyme present in almost all cells in our body and uses a majority of the oxygen that we breathe,” Gohil said.

This enzyme only works if it has copper in it, he explained. Without copper, the enzyme won’t function, and the body stops working due to lack of energy production.

Finding the drug

Gohil began working on this project in 2012, and in 2014 his team began focusing on elesclomol and showed that it can deliver copper to mitochondria and restore the production of cytochrome oxidase protein complex in copper-deficient yeast and human cells, as well as in zebrafish.

In 2017, Gohil’s graduate student Shivatheja Soma and postdoctoral fellow Mohammad Zulkifli, Ph.D., began collaborating with Guthrie, Andres Silva and others from the Sacchettini group. They began to translate the laboratory results into a preclinical mouse model of Menkes disease.

The team focused on developing procedures for using elesclomol to treat Menkes and optimizing treatment strategies to find the right doses.

“These were difficult and time-consuming experiments that required special precautions because we were working with very sick mice, ones that carried the same type of mutation as humans with severe Menkes disease,” Guthrie said.

“These mice showed very similar symptoms to babies with the disease. We had hope that if we could successfully treat these mice, we would be able to translate the discoveries to infants.”

Sacchettini said the first step was to overcome the side effects of using a cancer drug to treat the disease. The major breakthrough came when their group came up with a new way to prepare the drug.

“We found that by mixing elesclomol with copper in a special formulation, we could keep the new form of the drug soluble prior to administration,” he said. “With this approach we were able to dramatically increase survival of the mice and, importantly, to normalize their brain development.”

The collaborators from the University of Maryland, led by Byung-Eun Kim, Ph.D., showed that elesclomol could overcome more than just defects in the transporter that causes Menkes disease.

The medication also targeted a second copper transporter, one implicated in the development of hypertrophic heart and liver disorders in mice and humans—indicating the therapeutic applications of elesclomol may not be limited to Menkes disease.

Gohil’s group and Michael Petris, Ph.D., from the University of Missouri, showed that elesclomol escorted copper to different tissues and delivered it to copper-utilizing enzymes like cytochrome c oxidase in mitochondria.

Promising results

Through this mechanism, elesclomol prevented brain damage and improved the survival of Menkes mice from a mere 14 days to over 200 days.

While there is still more work to do in preparation for treating infants with Menkes disease, Sacchettini and Gohil say they are confident they will soon be able to extend the survival and quality of life for those born with this devastating disease.


Copper is an essential trace element involved in a plethora of biological processes in living cells. Analysis of human proteome identified 54 copper-binding proteins—of which, 12 are copper transporters, approximately half are enzymes and one (Antioxidant 1 Copper Chaperone, ATOX1) is a transcription factor [1].

Copper-binding proteins include cytochrome oxidase, copper-zinc-superoxide dismutase, lysyl oxidase, tyrosinase, and dopamine-beta-monooxygenase, which are involved in pivotal biological processes like mitochondrial respiration, antioxidant defense, extracellular matrix cross-linking, pigmentation and neurotransmitter biosynthesis, respectively [2,3].

For an accurate list of copper-requiring enzymes, with particular emphasis on enzymes involved in genetic disorders of copper homeostasis, refer to Horn et al. [4]. The majority of copper in the body is located in organs with high metabolic activity, such as liver, kidneys, heart and brain; approximately 5% of total copper is in the serum—of which, up to 95% is bound to ceruloplasmin (Cp).

Unbound copper behaves as a potent oxidant, catalyzing the formation of highly reactive hydroxyl radicals leading to DNA, protein and lipid damage [5]. Therefore, cellular copper concentration needs to be finely regulated by complex homeostatic mechanisms of absorption, excretion and bioavailability [6].

Upon absorption in the gastrointestinal tract, copper reaches the blood, where it is mostly bound to Cp. Copper transporter 1 (CTR1, SLC31A1), located on the cell membrane, is the main copper import protein; within the cell various metallochaperones receive and deliver copper to specific locations.

ATPase copper-transporting alpha (ATP7A) and ATPase copper-transporting beta (ATP7B) are key players in copper homeostasis being required for copper delivery to the secretory pathway and for efflux of excess copper from the cell.

Deregulation of this delicate balance that maintains copper homeostasis has been associated with the pathogenesis of several diseases [7,8]. Consequently, a continuously growing number of in vitro and in vivo studies suggest that copper-involving mechanisms may represent a potential therapeutic target for different pathologies.

Clinical Application of Copper Chelation Therapy
A chelator is a chemical compound able to selectively bind, due to its structure, a particular atom/ion, with the formation of a stable complex ring-like structure. Metal chelating agents are used as nutritional supplements, for designing radiopharmaceuticals, as additives for cleaning chemicals, cosmetics, plastics, fertilizers, growth supplements in aquaculture, and to remove toxic metals from soil and in the body (chelation therapy) [9].

For a detailed biochemical description of several copper chelating agents, the reader is directed to a previously published review [10]. Copper overload toxicity as well as clinically significant copper deficiency are rare and mostly associated with genetic defects of copper transport such as Wilson’s disease (copper overload) and Menkes disease (copper deficiency).

On the other hand, copper is an essential catalytic cofactor in redox biochemistry; consequently, copper dyshomeostasis leading to its unpaired distribution has been linked with several disorders including diabetes, neurological disorders and cancer [11].

Different chelating drugs have been shown to modulate copper levels by different mechanisms; in particular, penicillamine, trientine, and dimercaptosuccinic acid form complexes which are excreted in the urine, while tetrathiomolybdate promotes copper biliary excretion (Table 1).

In addition, administration of zinc salts has been suggested as maintenance treatment for Wilson’s disease; zinc interferes with the gastrointestinal copper uptake by inducing metallothionein, which chelates copper, preventing absorption and allowing for its excretion in the feces.

The use of copper chelating drugs such as trientine in Wilson’s disease and in cancer patients has been considered safe [12,13]; nonetheless, the specific risk–benefit ratio for each therapeutic indication should be carefully evaluated by additional randomized clinical trials.

Table 1 Main copper chelating drugs.

Compound NameAbbreviationChemical FormulaStructural Formula
D-penicillamine: (S)-2-amino-3-mercapto-3-methylbutanoic acidDPAC5H11NO2SAn external file that holds a picture, illustration, etc.
Object name is ijms-21-01069-i001.jpg
TetrathiomolybdateTMMoS4An external file that holds a picture, illustration, etc.
Object name is ijms-21-01069-i002.jpg
Trientine: triethylenetetramine dihydrochlorideTETAC6H18N4An external file that holds a picture, illustration, etc.
Object name is ijms-21-01069-i003.jpg
5,7-Dichloro-2[(dimethylamino)methyl]quinolin-8-olPBT2C12H12Cl2N2OAn external file that holds a picture, illustration, etc.
Object name is ijms-21-01069-i004.jpg
2,3-Dimercaptosuccinic acidDMSAC4H6O4S2An external file that holds a picture, illustration, etc.
Object name is ijms-21-01069-i005.jpg

Structural formulas collected from the DrugBank public database (http://www.drugbank.ca/).

The aim of the present review is to provide a global overview on the main different chelation therapy approaches which have been evaluated for the treatment of the diseases in which copper imbalance has a key role in the onset of the pathology, including genetic diseases of copper metabolism such as Wilson’s diseases [8], neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases [14], idiopathic pulmonary fibrosis [15], diabetes [16], and different forms of cancer [17].

Wilson’s Disease

Wilson’s disease [18], Menkes disease [19] and occipital horn syndrome [20] are human genetic disorders associated with the deregulation of copper-transporting ATPases. Menkes disease and occipital horn syndrome are due to mutations in the ATP7A gene, resulting in reduced levels of serum copper and ceruloplasmin [21,22].

The current treatment for Menkes disease is mainly based on parenteral administration of copper-histidine [23]. In contrast, Wilson’s disease is an autosomal recessive disease caused by mutations in both copies of the ATP7B gene [18,24] leading to excess copper in the body and characterized by a series of clinical manifestations which include liver failure, tremors and other neurological symptoms [25].

Therefore, to manage increased copper levels, Wilson’s disease patients have been treated with different chelating agents, including D-penicillamine, trientine hydrochloride and tetrathiomolybdate [26,27] (Table 2).

The goal of copper chelating therapy for Wilson’s disease is to remove copper accumulated in tissues (de-coppering phase) and to prevent re-accumulation (maintenance phase).

Introduced in 1956, D-penicillamine (DPA) [28], a dimethylated cysteine, mobilizes tissue copper stores and promotes efficient excretion of excess copper into urine, but this amelioration of copper balance is not followed by improvements in the neurological symptoms.

Instead, DPA treatment may be responsible for worsening patients’ neurological symptoms, due to a putative increase in brain copper level [29]. Furthermore, the use of DPA has been limited by hematologic and renal toxicities [30].

Therefore, DPA was replaced by alternative anti-copper agents such as zinc salt, introduced in 1960 [31] and trientine in 1980 [32]. Zinc salts decrease intestinal dietary copper absorption by inducing the synthesis of intestinal copper chelating peptide metallothionein.

Copper is therefore sequestered within the enterocytes and ultimately excreted into feces [33]. Zinc has been added in 1997 by US Food and Drug Administration (FDA) to the list of Wilson’s treatments as maintenance drug [34]. Dimercaptosuccinic acid (DMSA), an antidote to heavy metal poisoning, and DMSA analogues have been extensively used for Wilson’s disease therapy in China because of local availability and affordability [35].

The reported toxic side effects are reduced compared to that of penicillamine [36]; one of the major limitations of DMSA is associated with its inability to cross the cell membrane.

Table 2

Copper chelation therapy clinical trials for non-tumoral disorders.

ConditionNCT Number/ReferenceTrial PhasePatients EnrolledDrug/InterventionStatus
Wilson’s DiseaseNCT02273596II28WTX101completed
NCT03299829n.a.50TETArecruiting
NCT01472874n.a.8TETAcompleted
NCT01378182n.a.10MSC transplantcompleted
Alzheimer’s disease[60]n.a.34DPAterminated
NCT00471211 [61]n.a.78PBT2completed
Idiopathic pulmonary fibrosisNCT00189176I/II23TMcompleted
Diabetes MellitusNCT01295073II0TETAwithdrawn
NCT01213888n.a.5TETAterminated

Abbreviations: DPA: D-penicillamine; MSC: mesenchymal stem cells; n.a.: not available; NCT number: ClinicalTrials.gov Identifier; PBT2: 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol; TETA: trientine tetrahydrochloride; TM: tetrathiomolybdate; WTX101: bis-choline tetrathiomolybdate.

Triethylenetetramine (TETA), also known as trientine, was specifically introduced for the treatment of Wilson’s patients showing DPA intolerance [32]. Trientine has improved safety profile but lower cupreuremic effect compared to DPA.

An additional copper chelating agent is ammonium tetrathiomolybdate (TM), which is also able to significantly reduce copper absorption when administered with food [37]. Preclinical studies performed with TM have led to FDA approval for a clinical trial for the treatment of Wilson’s neurological disorders [37,38,39]. I

n a comparative clinical trial, a clear reduction of the number of patients with neurodegenerative disease in the group treated with TM was determined with respect to the TETA treated group [40]. Despite the potential efficiency and limited toxicity, the clinical use of TM is limited by instability of the ammonium formulation [4] and to low compliance due to frequency of dosing (6 times/day).

For these limitations, a derivative of TM, the bis-choline-tetrathiomolybdate, has been recently introduced and a new multicenter phase II study has been performed, demonstrating the efficiency of the drug with no cases of paradoxical drug-related neurological worsening [41].

Moreover, a phase III study comparing bis-choline TM with other copper chelating compounds has been started in 2018 [42]. In recent years, other compounds have been tested in animal models.

Among them, DMP-1001 {methyl 4-[7-hydroxy-10,13-dimethyl-3-({4-[(pyridin-2-ylmethyl)amino]butyl}amino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate} [43]; methanobactin [44], trientine delivered through liposomes [45] and curcumin [46].

These drugs, however, need further studies both in vitro and in vivo as they have not been used in clinical trials so far. An updated overview on the currently approved treatments for Wilson’s clinical manifestation is reported in several recently published reviews [27,47,48] focused on the efficiency, the side efaafects and possible combination therapies.

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