According to a recent study published in the medical journal Lancet, the highest annual incidence of fungal keratitis per 1 lakh people is reported in Southern Asia and India (accounting for over 50per cent of the total microbial keratitis cases). Fungal keratitis is a vegetative trauma to the eye that is caused by the infected vegetable matter such as plant leaves and often leads to fungal infection of the cornea.
According to the WHO, fungal keratitis is a leading cause of monocular blindness i.e, blindness in one eye, in the developing world. In an effort to develop a better antifungal strategy for fungal keratitis, an all-women team of IIT Delhi researchers led by Prof. Archana Chugh has developed a novel peptide-based antifungal strategy for enhanced Natamycin penetration.
“Even though the antifungal drug Natamycin, is FDA approved primary line of treatment, it suffers from significant drawback of low penetration and moderate efficacy. As a result, dosage frequency of the drug is very high (hourly basis) and therapy may be needed up to 6-8 weeks, bringing huge discomfort and blurred vision to patients. So, it became an issue of interest to us in resolving the penetrability issue of Natamycin,” says Chugh, Associate Professor, Kusuma School of Biological Sciences, IIT Delhi.
While Chugh has an expertise on peptide mediated delivery, it was Dr Sushmita G Shah, the Senior Consultant ophthalmologist who conceived, designed, initiated, conducted and analysed studies in the lab with the peptide — Natamycin conjugate. Shah has treated scores of patients suffering from fungal keratitis. “We further collaborated with Dr Shikha Yadav, Head, Animal Facility at NIB, Noida, who helped us in conducting animal studies at NIB. Three research scholars — Dr Aastha Jain, Harsha Rohira and Sujithra Shankar — have been an integral workforce in the studies,” she adds.
It has been over a decadelong effort for Chugh and Dr Shah with this project, right from conception to reduction into different levels of experiments. “The experiments actually began mid-2012, when we received a grant for Phase 1 from DBT, Government of India. The peptide-Natamycin conjugate was custom synthesised and employed for studies on human corneal epithelial cell lines. The results of animal studies showed higher penetration of Tat2 Natamycin with a five-fold increase than Natamycin. Further, 44 per cent animals treated with peptide- drug conjugate showed complete resolution of fungal keratitis in comparison to the 13 per cent of animals in the group treated with Natamycin alone, indicating better antifungal efficacy,” she adds.
India being agriculturally predominant, there is a high incidence of fungal keratitis (fungal infection) in the agrarian population, due to relatively high exposure to the infected plant parts during activities such as harvesting. Chugh says, “These peptides are known to have the ability to carry molecules with them in the cells. Therefore, when poorly permeable Natamycin was attached to the peptide, the formed complex showed better antifungal effect.”
They have successfully carried out in vitro studies using peptide drug conjugate followed by in vivo studies (animal studies in rabbits and mice). A pilot study followed by detailed animal study has also been carried out. But the journey was not an easy one. “Funding and regulatory approvals for conducting the clinical trials were a major hurdle. However, gradually it worked out for both lab experimental studies as well as animal work. Later, we even received funding from Nanomission, DST, Govt of India. Peptide conjugate synthesis strategy also posed many challenges,” she adds.
The team have now approached several important pharmaceutical companies to engage them in conducting clinical trials. “The present conjugate is an important example of peptide mediated drug delivery strategy as compared to the currently existing solution which contains only natamycin,” Chugh says, adding that, “it is too early to do the price forecasting for the conjugate as we are yet to set into clinical trial stage. Nonetheless, our objective remains that the drug is offered at an affordable price in a very competitive field of antifungals.”