Harnessing Genetic Suppression to Treat Rare Disease

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Through quirks of genetics, some people are naturally resilient to heritable diseases. Thijn Brummelkamp, Managing Director and founder of the Dutch startup Scenic Biotech, explains how the company is using this genetic resilience to treat rare diseases and cancer.

Heritable diseases result from genetic mutations that cause essential proteins in the body to malfunction. For example, people with the condition Niemann–Pick type C have mutations in proteins involved in the transport of cholesterol in the cell. This makes cholesterol build up in the body and causes problems with walking and cognition. 

However, some people with mutations that should cause disease show no sign of the illness. According to Brummelkamp — who is also a Professor at the Netherlands Cancer Institute — a big reason for this disease resistance is because of genes called genetic modifiers. 

This explains why some people that have a mutation in the gene that causes the disease have more severe phenotypes than other family members may have,” he told me.

Brummelkamp and co-founder Sebastian Nijman spun Scenic Biotech out of the Netherlands Cancer Institute and the University of Oxford in the UK in 2017. The company’s preclinical pipeline is focused on identifying genetic modifiers that can suppress the effects of rare diseases in the lab, and then developing antibody or small molecule drugs to activate them in patients.

Typically, people have looked at the defective gene and tried to correct the gene or process,” Brummelkamp said. “In this case, this is a new class of drugs.”

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While it may sound promising, the task of finding genetic modifiers that delay disease — also known as genetic suppressors — is a huge one. First, there are thousands of rare diseases, each one with a very small pool of patients to study. Second, finding people with effective genetic suppressors for these diseases is tricky because many healthy people don’t typically go for genetic screens.

For most human diseases, we do not know what the genetic suppressors are,” explained Brummelkamp. “Both clinical data and population genetics suggests that these genetic suppressors exist, but it has been really difficult to identify them.

Scenic Biotech uses single-cell screening in the lab to overcome this issue. The company takes billions of healthy human cells or cells containing mutations responsible for the disease of interest. For each healthy or diseased cell, Scenic uses a method called gene trapping to stop one of the genes in the genome from working, and uses fluorescent labeling to check how it affects the cell’s health. By doing this, the company can then build up a picture of which genes suppress the disease.

The idea is that we really get an overview of the genetics of a particular disease, so that is why we’re called ‘Scenic,’” Brummelkamp said. “We really hope to identify the ‘scene’ that is relevant.

One big challenge to approaches like this one is that human cells contain two copies of each gene. These can mask mutations and make the analysis very complex. To address this, Scenic screens special human cancer-derived cells that only have one copy of each gene.

scenic biotech rare disease

Scenic is currently focused on developing a treatment for Niemann–Pick type C disease, and has a list of potential suppressor genes that could be targets for new drugs. In addition, the company has identified a genetic modifier that could allow it to develop a cancer immunotherapy enhancing the effect of checkpoint inhibitors, which prevent cancer cells from evading the immune system. 

Genetic modifiers are already being targeted by several biotechs. For example, the US company Maze Therapeutics raised an impressive €173M ($191M) Series A last year to screen genomic datasets for new genetic modifiers. 

For Scenic Biotech, the presence of other companies in this space doesn’t worry them. “I don’t believe that we will be all fishing in the same pool,” Brummelkamp noted. “This could be applied in oncology, it could be applied in common diseases, in rare diseases and, of course, there are many different disorders and ways to look at them and ways to correct them.

While the field of genetic modifiers in therapeutics is still emerging, investors are already sharing in Brummelkamp’s excitement, demonstrated by Scenic Biotech’s €6.5M Series A raised early after founding.

We did not have a difficult time finding excited investors to start Scenic and I think it was the concept and the opportunity,” Brummelkamp told me. “It’s a timely moment now to identify these suppressors and see if we can develop them. It was a very risky and early idea but one with great potential.”

Despite having founded two biotechs in his career — Scenic Biotech and the Austrian company Haplogen in 2010 — Brummelkamp spends the majority of his working life in his academic lab, limited to one day per week at Scenic Biotech. “As a scientist, results are always exciting, whether they come from the Scenic side or the academic side,” he told me.

Nonetheless, Brummelkamp is enthusiastic about spinning out new companies based on his discoveries, bridging the gap between academic discovery and commercialization.

I think it’s very exciting. I’ve learned so much more in the last two years and also from my previous experience in biotech, than I could imagine,” he said. “It really gives me a bit of a better understanding of the biology and, on the other hand, of the challenges in biotech and pharma.

Images from E. Resko and Shutterstock

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