MICA: Development of new agents for the treatment of cryptosporidiosis

A recent clinical study in Africa and South Asia has found that cryptosporidiosis is one of the most significant causes of death and illness from diarrheal diseases amongst children in the developing world. Cryptosporidiosis is caused by a single-celled protozoan parasite; the predominant species infecting humans are called Cryptosporidium hominis and Cryptosporidium parvum. This parasite mainly lives in the cells in the gut wall and has a complex life-cycle. Infection occurs due to consumption of water or food contaminated with the parasites. Parasites are spread from an infected individual through their faeces. In people who are healthy and well nourished, the disease clears naturally within a couple of weeks. However, in people who are malnourished (particularly in young children) and people with an immune system that is not functioning properly (for example HIV/AIDS victims), the disease can have a much more significant impact. It is the major contributor to life-threatening diarrhea in young children, with 2.9-4.7 million cases in children under 24 months in sub-Saharan Africa and the Indian sub-continent, leading to more than 200,000 deaths per year. Cryptosporidiosis is also associated with malnutrition and stunted growth in children and probably causes chronic infections, which last for weeks or months. The only drug registered for the treatment of this disease is nitazoxanide, which is not very effective, especially in those patients who are most severely affected due to a weak immune system and/ or malnutrition.

Therefore there is an urgent need for the development of new drugs to treat: (1) children <24 months, especially those that are malnourished and with chronic diarrhea; and (2) immunocompromised children and adults with advanced AIDS and chronic diarrhea. Cryptosporidium may be the cause of as much as 75% of chronic diarrhea in this patient cohort.

We have discovered some chemical starting points that can be used for a drug discovery programme. We have a series of compounds that kill the parasites and also are very effective in clearing the parasites from rodent models of cryptosporidiosis. The compounds are thought to work through preventing the parasite making proteins. The aim of this project is to take these starting points and optimise them to make a molecule which has the potential to be a drug. This will require us to optimise multiple features of the molecule: its ability to kill the parasite, its ability to reach the sites in the body where the parasite resides without being broken down, and its safety. At the end of this project we hope to have a "preclinical candidate". This is a compound that we think should be suitable to enter human clinical trials. The steps after this project, prior to human clinical trials will be to make the compound on a larger scale under properly defined conditions and to carry out formal safety testing.

Cryptosporidiosis is one of the most significant causes of death and illness from diarrheal diseases amongst children in the developing world, as found by the Global Enteric Multicenter Study (GEMS), a case-control study conducted at 7 sites in Africa and South Asia, the most comprehensive study to date. It is the major contributor to life-threatening diarrhea in young children, with 2.9-4.7 million cases in children < 24 months in sub-Saharan Africa and the Indian sub-continent, leading to >200,000 deaths per year. Cryptosporidiosis is also associated with malnutrition and stunted growth in children and probably causes chronic infections. Nitazoxanide, the current treatment for the disease, has poor efficacy and is not effective in immunocompromised patients.

There is an urgent need for the development of new drugs to treat: (1) children <24 months, especially those that are malnourished and with chronic diarrhea; and (2) immunocompromised children and adults with advanced AIDS and chronic diarrhea. Cryptospordium may be the cause of as much as 75% of chronic diarrhea in this patient cohort.

We have developed a series of orally efficaceous compounds in two mouse models of cryptosporidiosis, demonstrating great potential to treat the disease. This series has been discovered through a structurally enabled programme for lysyl t-RNA synthetase. The series has been declared an "early lead" by the Scientific Advisory Board of the Structure Guided Drug Discovery Coalition. The aim of this project is to optimise the series to identify a preclinical candidate, orally active in appropriate animal models of infection (rodent and calf) and overall good developability properties for progression towards the clinic. This will involve optimising the compounds for potency against the parasite; for pharmacokinetics to ensure optimal compound delivery to the sites in the body where parasites reside; and for appropriate safety margins.

If the research is successful, it should have impact in multiple ways.

(1) Patients. Current treatments for cryptosporidiosis are poorly effective or in-effective. This is particularly the case for malnourished or immunocompromised children. This leads to a chronic disease and a high mortality rate. The chronic infection also can lead to problems in cognitive development of infants. New drugs which are effective against cryptosporidiosis should have a major impact on the health and development of infants and children, particularly in Low and Middle Income Countries. Another patient population poorly served by current medicines are immunocompromised patients, where the treatment is essentially ineffective.

(2) The Wider Community. New and better drugs to treat cryptosporidiosis will also have an impact on the wider community. Illness has a very significant impact on communities in Low and Middle Income Countries. Often patients may have to travel long distances to obtain medical help. They have to be accompanied by their families who have to care for them. This often has dire economic consequences for the family. Better treatment would have massive economic benefits. Further by more effectively treating disease this would reduce the overall incidence of disease within a community.

(3) Clinicians. Clinicians need new medicines to be able to tackle the diseases that they have to deal with. If our project eventually gives rise to new medicines, this will make a large impact for clinicians.

(4) Scientists. There is a need for a more fundamental understanding of cryptosporidiosis. This will come through the drug discovery process, where more fundamental understanding will occur. Also through the drug discovery process, we will provide tool molecules. These tool molecules will be very valuable in dissecting vulnerable parts of Cryptosporidium biology.

(5) Training. This project will provide training to scientists in anti-infective drug discovery. This is something that is under-represented within the UK.