Worms, Snail Divers, and Scar Tissue: Tackling the Mystery of Liver Fibrosis
By: Heather Arnett
Tags: Genetics, Uganda, Variant, Liver Fibrosis, Schistosomiasis

Bob Shaban, 37, holds a handful of freshwater snails pulled from the banks of Lake Victoria in Uganda. These small snails often harbor schistosomes, a parasitic flatworm that thrives in bodies of water contaminated by the feces or urine of an infected host. These worms can penetrate skin, leaving those who swim, bathe, or wash their clothes in contaminated water vulnerable to infection. Photo credit: WHO

Lurking in fresh-water rivers and waterways throughout the world is a type of small worm, called schistosomes, that live with and rely upon specific species of aquatic snails for survival. Highly prized for food, these snails are often harvested by divers, exposing the divers and anyone else who bathes or washes clothes in the river to the worms’ larvae. The larvae can easily penetrate skin, and even a short exposure to infested water can lead to infection.

Infection by schistosomes is called schistosomiasis or bilharzia, and it is particularly prevalent in tropical and subtropical areas of the world, primarily in communities without access to safe drinking water and adequate sanitation. Schistosomiasis affects almost 240 million people worldwide, with more than 700 million living in endemic areas. Around 90% of those requiring treatment for schistosomiasis live in Africa.¹ Schistosomiasis can usually be treated successfully with a short course of medication called praziquantel that kills the worms. The treatment is unfortunately not readily available or sought-after due to lack of awareness in many parts of the world.²

Schistosomiasis affects almost 240 million people worldwide, with more than 700 million living in endemic areas.¹ Different types of schistosomes are present in different geographical regions, and drive different types of disease. Urogenital schistosomiasis is caused by Schistosoma haematobium and intestinal schistosomiasis by any of the organisms S. guineensis, S. intercalatum, S. mansoni, S. japonicum, and S. mekongi. Our study focuses on S. mansoni infections. Image credit: Nature

Once an individual is infected, the worms mature in the bloodstream and lay eggs, which sets off a chain of events that can culminate in a type of permanent scarring of the liver, called fibrosis. Fibrosis, the laying down of an excessive extracellular matrix, is a body’s healthy response to an injury — and is required to heal wounds. But when fibrosis does not resolve, the excessive build-up of scar tissue in any organ can contribute to an inability of that organ to function. Fibrosis can occur in many different types of disease, and across many different organs — with lungs, skin, kidney, heart, and liver being some of the most problematic. Liver fibrosis is the primary pathology in various forms of liver disease — alcohol-induced cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH), and is also associated with various viral infections of the liver (e.g. Hepatitis B, C). To date, no treatments have conclusively shown the ability to reverse or halt fibrosis of the liver.

The life cycle of S. mansoni. Image credit: Nature

To tackle this area of unmet medical need, Variant Bio has partnered with Bilhi Genetics, founded by Dr. Alain Dessein, a pioneer in the genetics and treatment of fibrosis. Together, we aim to identify genetic risk factors for severe liver fibrosis among a particular community in Uganda. The participants were recruited from two settlements in the West Nile region with a very high prevalence of schistosoma parasites. They were recruited based on years of exposure to the parasite (bathing, fishing) and their livers were evaluated for fibrosis progression.

But fibrosis does not impact everyone equally — why do some infected with schistosomiasis develop severe, debilitating liver fibrosis, while others do not? Are some individuals more genetically predisposed to fibrosis than others? Intriguingly, a subset of the population we are studying in Uganda seems to be resistant to rapid fibrosis progression, despite being infected by schistosoma parasites. The underlying biology of fibrosis progression is known to be similar in schistosomiasis and diseases such as NASH. Therefore, our hope is that the genetics of these resistant individuals will help us uncover why some appear to be protected from an ongoing fibrotic response. Our goal is to identify novel, large-effect size, genetically validated targets for liver fibrosis, which will allow us to develop new drugs for diseases such as NASH and NAFLD.

Dr. Alain Dessein and his team have spent years working with communities along the banks of Lake Albert in Uganda and across the world, including in China, Sudan, Mali, and Brazil, setting up annual clinics to diagnose, treat, and monitor schistosomiasis. As he has noted, “Schistosomiasis, and the fibrotic response that accompanies it, is a profound problem in these communities. Understanding factors for genetic susceptibility to liver fibrosis will undoubtedly lead to more and better therapeutic options for them.”

Variant Bio will apply our expertise in analyzing whole-genome and whole-exome sequencing data to the samples sequenced by the Bilhi Genetics team. By including individuals with similar levels of exposure to the parasite, who were recruited by Dr. Dessein and his team, we can identify those with rapidly progressing and severe fibrosis and compare them to those with slowly progressing fibrosis. Analysis of the genetics of these two groups will enable the identification of genetic variants that put individuals “at risk” of severe fibrosis, as well as those that protect from fibrosis. We expect these findings to help us understand some of the fundamental biology underlying the pathogenesis of liver fibrosis, and also to enable a drug discovery research effort, driven by human genetics.

The common goal for Variant Bio, Bilhi Genetics, and the individuals taking part in the study is the development of better therapeutics for liver fibrosis, and better outcomes for the patients affected by this disease. As someone who has worked in drug discovery focused on fibrotic diseases for many years, the importance of research into fibrosis is difficult to overstate — up to 45% of deaths in the industrialized world can be attributed to fibrosis.³,⁴ We believe that understanding the genetics of schistosomiasis-induced liver fibrosis will direct us towards a cure not just for schistosomiasis, but for many different forms of fibrosis.