Genetically modified helminths as pharmaceutical biofactories

A myriad of diseases can be treated by efficacious and potent drugs, yet the delivery efficiency is often hindered due to absorption issues, loss during first-pass metabolism, non-specific delivery, degradation before action and failure to comply to treatment. This has motivated researchers to develop novel methods for drug delivery, including live biotherapeutic products, notably transgenic bacteria delivering foreign therapeutic molecules. Recent advancements demonstrate that controlled experimental human helminth infections are tolerated and safe and may have natural protective attributes for other maladies. Helminths continuously release a cocktail of excretory/secretory proteins (ESP) during infection to aid migration and feeding, and to modulate the host's immune system. Genetic modification, and most specifically Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and CRISPR-associated nucleases, has transformed the study and manipulation of the eukaryotic genome. Using these approaches to target regions of the helminth genome, it is now possible to genetically modify parasitic helminths to constitutively release therapeutic biologics. This approach could be applied to targeting diseases such as Inflammatory Bowel Disease, metabolic diseases such as type 2 diabetes, Coeliac Disease and arthritis, all of which represent a severe burden on both patients and the community. Here, we review the current evidence that wild type and genetically engineered helminths could serve as novel drug-delivery platforms. We specifically focus on species of human hookworms and schistosomes, following published controlled human infections and clinical trials in healthy and diseased human subjects.