Fighting disease

A small group of researchers are making big strides in combating kala azar

While the government talks of eliminating kala azar, these scientists are studying the parasite’s DNA and developing new drugs.

When Finance Minister Arun Jaitley declared during his budget speech this year that India would eliminate kala azar by the end of 2017, Dr Vikash Dubey and his colleagues at Indian Institute of Technology, Guwahati were working on developing a drug for the deadly disease. Dubey has been sifting through genomic data of the kala azar pathogen.

Kala azar or visceral leishmaniasis is caused by the leishmania parasite and transmitted by the female sandfly or balu makhi. The disease is characterised by irregular bouts of fever, weight loss, anaemia and enlargement of the spleen and liver that shows up as a pot belly in the patient. If not treated, the disease can be fatal.

India has been trying to eliminate kala azar since Independence. However, every time the government launched a programme fighting the disease is has only returned when the government efforts waned. Now, armed with an effective drug called liposomal amphotericin B, a rapid diagnostic kit and a sandfly control strategy, the government making another concerted push.

But scientists who have been studying kala azar for decades are sceptical about the 2017 elimination target. While commending the Kala Azar Elimination Programme in general, they say that it cannot rely on a single drug.

“We have only one drug and if this fails we are nowhere,” said Dr Shyam Sunder who runs the Kala Azar Research Medical Research Centre at Benaras Hindu University. Sunder has been treating kala azar patients, conducting scientific and epidemiological research and testing drug protocols for this disease for nearly three decades. He provides samples of the parasite to biochemists such as Dubey who are trying to develop new drugs.

Leishmania genome sequencing

Kala azar is endemic to four states – Bihar, Jharkhand, West Bengal and Uttar Pradesh. The Kala Azar Elimination Programme involves three-hour treatment with liposomal amphotericin B that is administered intravenously at a health centre.

India’s kala azar outbreak hit its peak in 2007 when there were 45,508 cases. Since then, the number of cases have dropped to only 6,245 last year. The drastic decline has made the government optimistic about eliminating the disease this year.

Meanwhile, many scientific developments have helped scientists understand the disease better.

In 2013, Dr Neeloo Singh and her colleagues at the Central Drug Research Institute in Lucknow published the entire sequenced genome of the leishmania parasite that causes kala azar. This has opened up new avenues to study the parasite and look for a cure to the disease.

“The world can now use the biological data,” said Singh. “So far, we did not understand how the parasite acts. After sequencing the genome, you know better how it acts and can design drugs accordingly. We can also understand drug resistance better.”

Singh explained that leishmania parasite develops resistance faster than other pathogens. Since the parasite affects the visceral systems and lodges itself in the spleen, it has more time to develop a shield around itself that protects from the anti-parasitic drugs.

Many Indians have developed resistance to the first known anti-kala azar drug sodium stibogluconate. Other medication, including liposomal amphotericin B, have side effects or are not easy to administer and require a patient to be hospitalised. Sunder pointed out that some studies indicate that a few patients have started developing resistance to liposomal amphotericin B as well.

“We still do not understand the immunology of the disease and understand patterns of drug resistance,” he said.

Dubey and his team have identified a chink in the leishmania parasite’s armour. They used what is called the gene knockout procedure that removes a gene that produces the protein CAAX prenyl protease II from the leishmania DNA. Leishmania cannot survive without this protein. Now Dubey and his colleagues are testing a molecule that can target the protein in the parasite.

“Earlier we were just testing compounds for anti-leishmania properties,” said Dubey. “They used to be random discoveries. Now that the genome is known, we can identify the gene unique to leishmania and design a molecule that only targets that gene, without harming humans.”

Dr Vikash Dubey who works on protein Biochemistry, biochemical parasitology and drug discovery at the Indian Institute of Technology, Guwahati. (Photo: Vikash Dubey)
Dr Vikash Dubey who works on protein Biochemistry, biochemical parasitology and drug discovery at the Indian Institute of Technology, Guwahati. (Photo: Vikash Dubey)

Similarly, the Central Drug Research Institute where Singh works has also tested Monastrol on mice infected with leishmaniasis. Monastrol was originally developed as an anti-cancer drug. In this experiment, the drug is being used to target the same protein CAAX prenyl protease II. If the results are positive, the researchers hope to conduct human trials for its use against kala azar.

Collaborating on kala azar

Kala azar is classified as a neglected tropical disease and, not surprisingly, not many scientists choose to work in this field. Dr CP Thakur, former union health minister and doctor at Patna Medical College, was one of the first doctors to conduct various drug protocols against kala azar in the 1980s. His work was followed by Dr Shyam Sunder and Dr TK Jha who ran Kala Azar Research Centre at Muzaffarpur in Bihar. In 1981, the Rajendra Memorial Research Institute of Medical Science in Patna was set up in 1981 with a mandate to work on kala Azar diagnosis, treatment and control.

When Singh joined Central Drug Research Institute in 1992, it was in the middle of a raging kala azar epidemic. “It was very moving when you go to see people suffer in the outpatient department of a hospital in Bihar,” said Singh. “Morality is the first factor. We were working on the tax payer’s money and were morally answerable to choose the areas we choose.”

Dr Neeloo Singh who has sequenced the leishmania genome. (Photo: Central Drug Research Institute)
Dr Neeloo Singh who has sequenced the leishmania genome. (Photo: Central Drug Research Institute)

Singh also helped set up the Leishmaniasis Research Society of India in Lucknow and has won an award from the Indian Council for Medical Research in 2012 for her work. Singh said that many young researchers do not choose to work on kala azar because they are also scared of getting infected by the parasite. There are also no quick results in kala azar research. Unlike other pathogens, leishmania is notoriously difficult to grow in a laboratory. The samples are drawn from spleen or bone marrow in tiny portions. “If I culture about 20-30 isolates, it will be my good destiny if three or four grow in the laboratory,” she said.

The few kala azar researchers, however, collaborate and are not competitive unlike research communities that work on other diseases such as malaria.

More recently, organisations like the medical charity Medecins Sans Frontieres and the Drugs for Neglected Diseases Initiative have started investigating protocols for liposomal amphotericin and have designed the protocol that is used in the Indian government’s programme. The two organisations are now working on testing various drug protocols for patients suffering from HIV-kala azar co-infections and post-kala azar dermal leishmaniasis – a skin manifestation of kala azar.

Before these international organisations started work on the disease, most of the research was funded by the Indian government. Some kala azar projects are now funded by the Bill and Melinda Gates Foundation and the United Kingdom Department for International Development. With support now coming from the Centre for Disease Control in the United States, India’s kala azar researchers are getting access to advanced laboratory technologies in the US that helps their work.

“We are in a much better situation than earlier (in terms of controlling the disease),” said Singh. “But we still do not have a foolproof drug or diagnostics for this disease. We definitely need more drugs and diagnostics.”

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