Overview

Malaria is a deadly disease that causes around 405,000 deaths globally every single year. ^[1] The current treatment is Artemisinin Combination Therapy (ACT), which relies on the usage of Artemisinin, a potent drug used to combat malaria, along with a few other medications. However, resistance to Artemisinin is fast rising, and this is a huge issue, especially for South Asian and African countries, who have a huge load of global Malaria cases.

The first part of our project aims to design a inhibitory peptide drug that would target a protein-protein interaction which is necessary for the spread of the disease in the human body. This peptide would act as a competitive inhibitor to the interaction, thus preventing the spread of the disease in the body. The short, inhibitory peptide will be engineered into a cyclotide - a circular, protease resistant, highly stable plant-derived protein, which will serve as our method of drug delivery.

The second phase of our project has been the development of a simple, diagnostic kit with three components - an easy-to-assemble foldscope, a paper centrifuge that can be used to prepare blood smears, and a Deep Learning software that can analyze images of blood smears and classify the samples as infected or uninfected.

The proposed end users of our project would be common people who suffer from Malaria. In 2018, the economic burden of Malaria was over 11,640 crore rupees ($19.4 billion). ^[2]

Therapeutics

As with any drug development endeavour, the proposed implementation of the first phase of our project will involve multiple years of work before the drug can be brought to a market. The process of drug development goes through many phases after the actual drug has been discovered.

Lead Molecule Optimization:

Our discovered drug will need to undergo optimization trials to measure the physio-chemical properties of the candidate drug. Apart from this, the drug’s Adsorption, Digestion, Metabolism and Excretion (ADME) profile needs to be studied. This is important to understand how the drug would interact in the human body.

‘Lipinsky’s rule of five’ serves as a rule of thumb that can help assess whether the proposed molecule could be administered as an orally active drug in humans. These criteria serve as markers for the drugs pharmacokinetic properties in the human body.

Preclinical Trials

Preclinical trials are important to establish safety of the drug before it goes through clinical trials. Both in-vitro and in-vivo assays help establish the safety of the proposed drug. Cultured cells and laboratory animals are used for the same. The proposed drug is also subjected to toxicity and carcinogenicity profiles.

Toxicity trials can also give us an idea about the dosage of our drug that is required. Once these tests are over, the drug needs to then be approved for clinical trials by the regulatory board of the country.

Clinical Trials

Clinical trials occur in phases, and are necessary for the drug to become freely available in the market.

Phase 1:In Phase 1 clinical trials, the drug will be tested on healthy volunteers. This is done to understand potential side effects of the drug.

Phase 2:In Phase 2 clinical trials, multiple doses of the drug are tested on 300-500 volunteers who have the targeted disease.

Phase 3:In Phase 3 clinical trials, large numbers of people will take multiple doses of the drug for a longer period of time. This is done to check for the efficacy of the drug and potential long-term side effects.

Phase 4:In the final Phase 4 clinical trials, larger populations test out the drug, and all previous data for safety will be checked.

The data from all these clinical trials will then be submitted for approval by the regulatory board of the country.

With regards to how our team plans to do this moving forward, current plans are to keep performing the basic required research past the iGEM competition. We are also looking into the application of grants that would help us do the same. Based on the results that we are able to obtain, there are multiple paths to take this forward.

During our conversation with Dr. Velavan, he mentioned the name of organizations such as the Medicines for Malaria Venture (MMV) that we could potentially tie up with/ submit our results to. There are other for-profit pharmaceutical companies we could potentially sell/ share our work with. Dr. Velavan also mentioned that some of these pharmaceutical companies also maintain databases of online protein interactions between Plasmodium and human proteins, and we could add to the research available and/ or collaborate with other researchers on taking this project forward.

Depending on the results we obtain and the research we manage to do, our team is also discussing the possibility of creating a start-up. Due to the situation this year and the resultant lack of laboratory work that has been possible so far, all these decisions will have to be taken only in the future.

Diagnostics

From a software perspective, there are certain improvements we want to make before performing field trials with our kit. A lot of this feedback was received through our integrated Human practices interview with Poornima Raveendran, which you can find here. Currently, our software is able to recognize only RBC images that have been cropped and processed in a method comparable to the images in the dataset we used to train our model. A definite improvement that needs to be made is that the image identification software needs to be able to identify the RBCs from a given field of view and preprocess them without human intervention.

We are also looking into whether it would be possible to develop the software further so it can calculate Percentage Parasitemia . Percentage Parasitemia refers to the percentage of RBCs in a given blood sample that are infected. It is helpful from a medical point of view.

We also wish to develop an android application that can work on all sorts of mobile devices using the model we’ve developed so far. Keeping in mind internet constraints that would exist in remote areas that have a huge Malaria burden, we want to keep the size of such an application small and ensure that the app can make diagnoses offline.

From our talk with Sriram Raghavendran, we decided to split our diagnostic kit into two components, that of a Reusable kit, the constituents of which could be used for multiple tests, and a Consumables kit, which would contain a limited set of per patient disposables. Every healthcare center/ testing center would get one Reusable kit and these Consumables kits could be resupplied as and when necessary. We are also looking into whether it would be possible to ship out assembled foldscopes instead of unassembled ones, as this would reduce the burden on healthcare workers to set up the kit.

We also took feedback from doctors who had previously worked at/ currently work at rural Primary Health Centres (PHCs). They recommended we ensure that any videos we make get translated into vernacular languages so we can reach the most people. This is definitely something we plan to do.

As for how we plan for this kit to reach the most number of people, we need to conduct field trials to ensure it works well. We recently spoke to doctors at a healthcare organization and we are in talks with them to conduct mass level tests with our diagnostic kit. This project has been an undertaking of a lot of effort by all our members and we hope to take it forward to fruition, envisioning a world free of Malaria.

References

[1]: World Health Organization: WHO. (2020, January 14). Malaria. Link

[2]: Dey, S. (2016, February 18). Malaria costs India Rs 11,640 crore yearly, dengue Rs 6,000 crore: WHO. The Times of India. Link