Nitisinone, a drug used to treat rare diseases (such as tyrosinemia type 1 and alkaptonuria), has revealed a surprising property: it can kill mosquitoes, especially those that spread malaria. The discovery, published in Science Translational Medicine, could pave the way in the fight against this deadly disease, which still affects millions of people worldwide.
Nitisinone: what it is and why it kills mosquitoes
Nitisinone is a medicine used to treat rare genetic diseases in which the body cannot metabolise the amino acid tyrosine properly. In these diseases, toxic substances build up and damage key organs such as the liver. Nitisinone blocks a key enzyme, preventing this accumulation and protecting patients’ health. But researchers also discovered that the medicine has another, completely unexpected effect: it kills mosquitoes. Mosquitoes such as Anopheles gambiae—the species that transmits malaria—suck blood from people who have been given the medicine, and once inside their bodies, nitisinone blocks the same enzyme that it blocks in the human body, preventing the mosquitoes from digesting the blood properly. As a result, the mosquitoes die quickly. This effect has also been observed in adult mosquitoes and those that have developed resistance to traditional insecticides.
Malaria is one of the world’s most devastating diseases, causing hundreds of thousands of deaths each year, predominantly in Africa. Currently, drugs such as ivermectin are used to reduce the life span of mosquitoes, but they have limitations, including the risk of creating resistance in parasites and being toxic to the environment. Nitisinone, on the other hand, has a longer-lasting effect and could be a safer, long-term solution. It could also be combined with ivermectin in some areas to maximise mosquito control efficacy, particularly in areas where ivermectin is no longer effective due to resistance.
What is the potential of nitisinone? We talk to Annalisa Bruno
Scientists are now preparing field trials to find the right dose of nitisinone that can be used effectively without harming people: this could become a new way of controlling malaria, offering a low-cost and sustainable option. In the future, nitisinone could really make a difference in the fight against mosquito-borne diseases.
To find out more, we spoke to Annalisa Bruno, a lecturer in pharmacology at UniCamillus University.
Nitisinone works in humans and mosquitoes by inhibiting HPPD. In mosquitoes, however, it is lethal. What is the difference in the mechanism of action?
“Nitisinone is a competitive inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), which is involved in tyrosine metabolism. It is used therapeutically in patients with hereditary tyrosinemia type 1 (HT-1) and alkaptonuria (AKU). In these rare genetic diseases, the deficiency of enzymes involved in the final stages of tyrosine metabolism leads to the accumulation of toxic metabolites that are responsible for the clinical manifestations of these diseases, including kidney and liver damage. Treatment with nitisinone by inhibiting HPPD, an enzyme in the tyrosine pathway, prevents the formation of downstream toxic metabolites but increases circulating tyrosine levels.
In humans, HPPD inhibition by nitisinone is tolerated because tyrosine accumulation can be managed with a low tyrosine/phenylalanine diet and the tyrosine pathway can be clinically controlled and monitored.
Mosquitoes have no effective way of disposing of excess accumulated tyrosine, so when they feed on nitisinone-containing blood, inhibition of the HPPD enzyme causes toxic accumulation of tyrosine, leading to lethal tissue damage, paralysis and death”.
Nitisinone does not appear to be harmful to humans. What are the known side effects?
“Available information on the safety of nitisinone is not entirely clear due to the rarity of the genetic disorders for which it is recommended (HT-1 and AKU), which involve small patient cohorts. Nitisinone is approved for use in infants and young children. No adverse events have been reported in pregnancy. Increased serum tyrosine concentrations may cause ocular side effects such as keratopathy, conjunctivitis, corneal opacity and ocular pain. Other common adverse reactions include thrombocytopoenia, leucopoenia and granulocytopoenia. Infections, headache and cognitive impairment have also been reported, with a higher incidence in patients treated with nitisinone than in untreated patients. The systemic effects of chronic tyrosine accumulation on other major tissues and organs are unknown”.
What might be the next steps in this trial?
“The results of this trial suggest that the lethal effect of nitisinone on Anopheles mosquitoes—which transmit the Plasmodium parasite responsible for malaria—could be a successful intervention strategy to prevent disease transmission. Further development of this trial should include further evaluation of the safety profile of the medicine, particularly in healthy people. This is essential to determine an appropriate medication regimen. In addition, its lethality should be tested in other blood-feeding insects that act as vectors for human pathogens. This would allow nitisinone to be repositioned for the control of multiple mosquito-borne diseases, reducing the cost of the medicine and thus increasing its availability for the treatment of rare genetic diseases”.
So, in addition to malaria, could nitisinone be used to control other insect-borne diseases such as dengue or Zika?
“The accumulation of tyrosine in mosquito tissues, caused by inhibition of the HPPD enzyme, leads to insect death, making nitisinone an interesting substance for mosquito population control. This approach could also potentially reduce the transmission of viral infections such as dengue, Zika and chikungunya, all of which are transmitted by mosquitoes, particularly the Aedes aegypti species. The lethal effect of nitisinone on mosquitoes could then be used to reduce the vector population, thereby reducing the likelihood of virus transmission”.
Do you think it can be used on a large scale, or are there patients who cannot use this drug?
“As pharmacological safety issues remain to be clarified, the use of nitisinone requires monitoring of circulating tyrosine levels to control toxic effects associated with its accumulation. Monitoring of platelet and leukocyte counts is also recommended due to the risk of thrombocytopoenia and leukopoenia, which may limit the use of the drug on a large scale. In addition, a low-protein diet is required during nitisinone therapy to limit the increase in tyrosine levels associated with HPPD enzyme inhibition. This may be another critical issue for large-scale use, particularly in malaria-endemic settings. In conditions that require high protein intakes, such as rapidly growing individuals or athletes, the required low-protein diet may be difficult to implement, which could impact on quality of life or treatment efficacy”.