MICA: Development of new agents for the treatment of cryptosporidiosis

Lead Research Organisation: University of Dundee
Department Name: School of Life Sciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Whilst this grant is at an early stage, we are developing a deeper understanding of the properties that will be required for a potential drug for cryptosporidosis. This will help us as we go forward in the drug discovery process. Ultimately this will facilitate developing a new medicine, which is urgently required in Low and Middle Income Countries
Exploitation Route The learnings should help us and others doing drug discovery to find a potential new medicine for cryptosporidiosis
Sectors Pharmaceuticals and Medical Biotechnology

 
Description The grant is at a very early stage. However we developing the drug discovery pathway for cryptosporidiosis. This will ultimately have an effect on SDG3, Health and Well-being. In terms of gender equality, the people mainly affected by cryptosporidiosis are young children and infants. This affects both genders and if a new medicine is developed it will be used equally for both male and female. In terms of people employed on the grant, there is a good gender balance
First Year Of Impact 2019
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Eisai 
Organisation Eisai Ltd
Department Eisai Inc
Country United States 
Sector Private 
PI Contribution Eisai is the Industrial Partner on our MICA award
Collaborator Contribution Eisai is the Industrial Partner on our MICA award and will contribute in areas such as safety pharmacology
Impact They are assisting in the development of compounds for cryptosporidiosis
Start Year 2019
 
Description University of Vermont 
Organisation University of Vermont
Country United States 
Sector Academic/University 
PI Contribution We have been working with Prof Chris Huston at the University of Vermont for a number of years. We are preparing compounds with potential activity against Cryptosporidium species and he is testing them in whole cell assays and in a mouse model of cryptosporidiosis. He is a co-applicant on the award.
Collaborator Contribution We have been working with Prof Chris Huston at the University of Vermont for a number of years. We are preparing compounds with potential activity against Cryptosporidium species and he is testing them in whole cell assays and in a mouse model of cryptosporidiosis. He is a co-applicant on the award.
Impact By working together we have produced a paper, which was published just prior to this award commencing www.pnas.org/cgi/doi/10.1073/pnas.1814685116
Start Year 2016
 
Title Drug Discovery for Cryptosporidiosis 
Description We are working the development of novel drugs for the treatment of cryptosporidiosis. At the moment the project is in lead optimisation 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2020
Development Status Under active development/distribution
Impact We are learning about the drug development pathway for new drugs for cryptosporidiosis through the work that we are carrying out. 
 
Description Careers Hive at National Museum of Scotland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Careers Hive is an immersive careers education event designed to give students in S1-S3 a new way to think about their futures. It highlights the opportunities available to those who study STEM subjects (science, technology, engineering and maths), as well as the cross-disciplinary skills and subjects that can support and enhance STEM careers. Richard Wall from the Mode of Action group spoke that this event.
Year(s) Of Engagement Activity 2019
 
Description Drug Discovery and Design 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This was an event to engage with the general public around the science that we are doing. There were various hands-on activities for children
Year(s) Of Engagement Activity 2019
URL https://wcair.dundee.ac.uk/events/drug-design-drug-discovery/
 
Description Girl Guides, Wander the Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Providing educational, inspirational and fun events and activities for the Girl Guides to participate in and learn about science, with a bias in some activities towards drug discovery research. The intended purpose of the event was to stimulate interest in science in young people by providing fun and educational activities and demonstrations as well as a forum to ask questions. The event sparked questions and discussion amongst more than 700 girl guides and leaders, with the leaders reporting a significant impact and an increased interest in science amongst the participants. 289 Girl Guide 'Medicine Maker' badges were also sold on the day. Malcolm Taylor
Year(s) Of Engagement Activity 2020
URL http://www.girlguidingscotland.org.uk/event/wander-the-world-edinburgh-edition/
 
Description In conversation with Ian and Kev: Industry, Academia and Drug Discovery 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a discussion around career paths for 2 members of the Senior Leadership Team of the DDU, Ian Gilbert and Kevin Read
Year(s) Of Engagement Activity 2021
 
Description Medicine Maker 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Title: Designing a 'Medicine Maker' badge for Girlguiding UK

Engagement Activity: Designing activities to teach Girl Guides aged 5 -14 about the drug discovery process. This involved designing suitable practical activities to illustrate each stage of the drug discovery process, writing a pack for leaders with suitable instructions, running 'launch' events for local Girlguiding groups to try out the activities and running tours of our labs so they could meet some real women in science.

People reached: ~30 girls and leaders from local girlguiding units attended launch events to try out the activities. The badge and pack were advertised nationwide and so far more than 750 have been sold (for a nominal fee, to cover cost of badge production). The primary target for this project was girls aged 5-11 and adult leaders who were interested in running the activities.

Time: Launch events, leaders' events and demonstrations of the activities have taken place throughout 2019. The girls were excited to try out the hands-on activities and seemed very interested, asking lots of engaging questions. Feedback from leaders who have tried out the activities with their own units has been very positive.

Impact: Getting younger audiences interested in science and giving them an appreciation for how new medicines are made.
Year(s) Of Engagement Activity 2019
URL https://doi.org/10.20933/100001135
 
Description Medicine Maker Girl Guiding Badge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Medicine Maker badge is a large suite of activities designed to encourage girls and women to participate in science, while informing them about the Wellcome Centre for Anti-Infectives' work. It was inspired by a perceived lack of science in the new Girlguiding programme by a group of guide leaders from within the organisation.
A team of researchers from across the centre devised the activities. They included games, crafts, poster-making, practical experiments, and more. They were planned to suit a wide range of ages, from the youngest rainbows up to adults.
Since our launch event in early 2019 over 700 badges have been ordered by Girlguiding units from around the UK. We are continuing to work with Girlguiding Dundee to maintain our links, and keep providing their members with easy access to science. Feedback so far has been very positive, with many of the drawing activities showing how engaged participants have been.
The team behind the development of the badge won the Brian Cox Prize for Public Engagement, Project of the Year 2019.
Year(s) Of Engagement Activity 2019
 
Description Parasiteseeing: Departure Lounge (LifeSpace: Science Art Research Gallery exhibition) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This was a science art exhibition, created as a collaboration between artists from the University of Lancaster and scientists from the Wellcome Centre for Anti-Infectives Reseach. Set up as a 'travel blog' written by one of the parasites the Centre fights, it attracted over 500 visitors.
Scientists acted as a source of information and inspiration for the art, as well as providing technical support on some of the microscopy elements. The work has since toured to Dundee Science Centre and we have ambitions to take it further around the world, to disease-endemic countries.
Feedback from the exhibition showed that audiences had learned more about the parasite and disease it causes, as very few had had much previous knowledge. It also showed that the public saw the scientists as real people carrying out a worthwhile mission, and an increased closeness to science.
Year(s) Of Engagement Activity 2019
URL http://lifespace.dundee.ac.uk/exhibition/para-site-seeing-departure-lounge
 
Description Street Food 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Gave tours of the DDU screening facility. Public was 18+ years old, about 60 local people attended the event and about 20 went on the tour. Annual event to invite local adults into our building and learn about aspect of science that impact their daily life.
Year(s) Of Engagement Activity 2017,2018,2019
URL https://wcair.dundee.ac.uk/events/street-food-3/