Nitisinone isn’t just fighting AKU, it’s fighting mosquitos!

by | Jul 7, 2022 | Rare disease world

This week’s blog was written by Dr. Lee Haines. Dr. Lee works with Dr. Álvaro Acosta-Serrano, who leads a research team at the Liverpool School of Tropical Medicine (LSTM). The team is working to reduce mosquito populations by using the drug, nitisinone, which is currently being used to treat black bone disease or alkaptonuria (AKU). Learn more about this promising research now!

When a persistent mosquito decides you will be her midnight snack, what do you do? Do you spend countless hours waving a flip flop, newspaper, towel or pillow, just waiting for the opportunity to smack that high-pitched hum into oblivion? Does it infuriate you that if she manages to drink your blood, she perpetuates her species and ensures a future of sleepless nights?

Work presented by Dr. Álvaro Acosta-Serrano, who leads a research team at the Liverpool School of Tropical Medicine (LSTM), showed an unexpected way to kill mosquitoes that is counterintuitive to smacking them – let them drink blood from someone who is on a daily dose of nitisinone.

Image credit: Marissa Rafuse-Brown

Reducing mosquito populations is an essential part of controlling malaria and other diseases spread by blood-feeding insects and ticks. To understand the devastating impact of malaria, envision three Wembley Stadiums filled to capacity (approx. 270,000 people). For each person in the crowd, a child less than five years of age died of malaria just in 2019. There is no doubt why the tiny mosquito is named the most dangerous animal on earth.

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The two most effective methods for killing mosquitoes are either spraying insecticide onto indoor walls or using insecticide-treated bed nets. However, in recent years, mosquitoes have developed resistance to all insecticide classes and can now survive exposure to insecticide-coated walls and nets. Unfortunately, this is now causing a global resurgence of malaria cases and human deaths.

Dr. Acosta Serrano’s team, and colleagues from Brazil, Argentina and the UK, previously demonstrated a potential alternative to using neurotoxic insecticides; the beta-triketones represent a class of herbicides that cause photobleaching in plants and block a key enzyme that blood-feeding insects need to digest blood. Nitisinone is a potent beta-triketone. Spiking blood with nitisinone and feeding this to a blood-feeding insect first causes loss of flight, paralysis and finally liquification of the insects’ internal tissues.

Image: A cage of mosquitoes containing females filled with sugar or blood. Credit: Lee Haines

Using tsetse flies, this process was captured with time lapse videography on a cage of tsetse either recently fed on blood alone or blood spiked with nitisinone. In less than 24 hours, all treated flies were dead.

Sterkel M, Haines LR, Casas-Sánchez A, Owino Adung’a V, Vionette-Amaral RJ, Quek S, et al. (2021) Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis. PLoS Biol 19(1): e3000796.

As a first step, to expand the lab experiments using human blood, Dr. Acosta Serrano joined forces with Professors Ted Lock and Lakshminarayan Ranganath (also known as “Dr. Ranga”), and the National Alkaptonuria Centre based in the Royal Liverpool University Hospital (RLUH), to determine if people who are daily treated with a low dose of nitisinone had mosquitocidal blood. A single tube of blood from each donor was fed to a cage of hungry mosquitoes and mosquito death rates were tracked over time.

A talented LSTM PhD candidate, Ms. Anna Trett, raised all the mosquitoes for these experiments and worked with the fabulous NAC team and several brilliant AKU donors who gave up a tube of their blood for science. To our great delight, Anna’s experimental results matched our predictions; people with AKU taking a dose of 2 mg nitisinone per day, had extraordinary blood that killed mosquitoes within 18 hours.

Expanding the use of nitisinone beyond the treatment of tyrosinaemia and alkaptonuria, to include a novel way to help control malaria, is why Álvaro’s team continues to gather data. Not only does nitisinone provide a new alternative to the current suite of neurotoxic insecticides on the market, but it also has no effect on non-target insect species, such as pollinators (bees, bumblebees and nectar-feeding mosquitoes). This makes it more attractive to develop into a new tool to help control the mosquitoes spreading malaria.

PhD candidate Anna Trett showcasing her insectary and all the caged mosquitoes feeding on donated blood. Photo credit: Lee Haines.

So, now being trapped in a room with an annoying mosquito hungry for your blood may not hold such desperation. Indeed, this situation may cause a smile to escape your lips. Should nitisinone course through your veins, you will no longer be her midnight snack, but rather, her last supper.

The female malaria-transmitting mosquito, Anopheles gambiae, after feeding on a dye that makes her glow in the dark under a black light. Image credit: Lee Haines