In the 1970s, two researchers from the University of Texas Southwestern began studying a rare metabolic disorder known as familial hypercholesterolemia. These patients presented with intriguing symptoms, including extremely high levels of cholesterol in the blood. They often suffered heart attacks at a young age.
Through this rare disease research, the two biochemists, Dr Michael Brown and Dr Joseph Goldstein, discovered cholesterol was regulated through the LDL receptor. The findings earned the researchers a Nobel Prize and formed the basis for the development of one of the world’s most prescribed class of drugs: statins.
Rare disease research leads the way for drug innovation in gene therapy and cell therapies
What started as research into a rare disease ended up revolutionising the treatment of cardiovascular disease, the number one cause of death in the world.
“These rare disease studies opened up the whole pathway of cholesterol metabolism and led to some of the most profitable drugs in history, which have saved millions of lives treating and preventing cardiovascular disease,” says Dr Anne Pariser, director of the Office of Rare Diseases Research at the US National Institutes of Health’s National Center for Advancing Translational Sciences.
But this isn’t a standalone case study. Rare disease research has the potential to shine a light on a multitude of common health conditions and normal body functions, from blood clotting and ageing to autism and cancer.
Genetic links
“The study of these rare diseases is incredibly important for identifying cellular and molecular pathways that lead to the development of the disease,” explains Dr Fuki Marie Hisama, professor of medical genetics at the University of Washington School of Medicine in Seattle, US.
That benefits rare disease patients, she notes. However, many rare diseases are severe forms of a common disease, while other common conditions, such as cancer and dementia, can be broken down into rare subtypes. Such research “could yield new insights into understanding and then treating the [common] disease”, Hisama says.
This is because about 80% of rare diseases are genetic, with many arising from a mutation in a single gene. Understanding the gene, the protein it encodes and the function that protein performs in the cell can provide insights into the molecular pathways that control the biology of our cells. In turn, this can help us understand normal biological processes like metabolism, cell growth and division – important in cancer development – and even ageing. Common diseases can also share many of these genetic pathways, shedding light on the disease processes and providing targets for the development of new drugs.
That’s been true of research into the rare disease tuberous sclerosis complex (TSC), which causes non-cancerous tumours to develop in different parts of the body. Research into the disease found that the genes involved in TSC normally control a cell growth pathway, which is overactive in TSC because of the faulty genes.
“It was the linking of the TSC proteins to mTOR signalling, a key regulator of cell growth, that helped advance research and treatments for TSC patients,” such as the mTOR-targeted drug rapamycin, says Dr Elaine Dunlop, TSC researcher at Cardiff University in Wales.
The mTOR pathway is also activated in cancers, making things interesting from a broader health perspective. There’s been a lot of interest in using rapamycin as a cancer therapy, says Dunlop. “The importance of the TSC/mTOR pathway in cell growth has meant there are a number of scientists working in the field, which has been beneficial for a better understanding of the molecules controlling cell growth, which in turn helps us to understand both TSC and cancer better.”
Another rare disease with the potential for broader health benefits is Hutchinson-Gilford progeria syndrome, which is characterised by premature ageing, such as wrinkled skin, hair loss, hypertension, hardening of the arteries and heart failure. Understanding the function of a faulty protein in the disease could provide insight into the ageing process in the general population, as well as helping identify targets for the treatment of cardiovascular disease.
A complex path
Rare disease research is also benefiting health more broadly through the acceleration of drug innovation. The first chemotherapies, for example, were for rare blood cancers. Now, as genetics and genomics improve, rare diseases are at the forefront of personalised or precision medicine because their single genetic mutations allow for precisely targeted drugs.
“Rare disease research leads the way for drug innovation in gene therapy and cell therapies,” Pariser says, with the two approved gene therapies in the US both for rare diseases. The same principles can now begin to be applied to more common conditions, she says.
But the path forward has its challenges. Perhaps most importantly, there is still a limited understanding of the underlying biology for many rare diseases. “There are more than 7,000 rare diseases that have been discovered but many are not yet known to be linked to common diseases,” which makes it harder to discern the broader potential benefits, says Hisama.
The study of these rare diseases is incredibly important for identifying cellular and molecular pathways
Indeed, the picture is further complicated by the complex nature of genetics and genomics. The same mutations can sometimes result in different diseases, while common conditions can actually be rare subtypes with mutations affecting multiple genes, she adds. In both cases there may be no single common pathway to target for drug development.
Dr Richard Thompson is chief executive of the UK rare disease charity Findacure. He’s concerned that there aren’t enough researchers doing rare disease research because of the lack of incentives. Thompson thinks the means are there to find links between rare diseases and more common conditions through the scientific literature and the use of artificial intelligence. However, he wonders if the appetite exists.
Part of this comes down to funding. Rare diseases are often considered a poor relation when compared to more common conditions with larger patient populations.
Securing funds
However, while rare diseases might seem niche at first glance, lacking relevance for most people, Dunlop thinks that emphasising the links between rare diseases and common health conditions can help pull funding into the sector.
“Many funders, understandably, want their money to go towards research that will benefit as many people as possible, but there are opportunities for funding more rare disease work to help our understanding of some fundamental biological pathways and develop targeted treatments that could have a wider impact.” Dunlop’s TSC research is a case in point, where the link to cancer has seen more money invested in studying the biology than would have been available through TSC-focused charities alone.
Greater creativity and collaboration are key to encouraging a more permissible funding environment, says Thompson. Research should “look at pathways in common between diseases and then fund research for the pathway, which would help both rare diseases and common health conditions,” he adds.
The future of medicine lies in a genomic revolution. Rare disease research can lead the way. We all have DNA in common and we all have mutations, even if we’re not immediately aware of them, says Pariser. That’s why some people have severe side effects to drugs and why some suffer from Covid, yet others get no symptoms at all.
Building our knowledge of rare diseases would benefit everyone, she says. “Understanding rare diseases, mutations and pathways – that’s important to all of us.”
In the 1970s, two researchers from the University of Texas Southwestern began studying a rare metabolic disorder known as familial hypercholesterolemia. These patients presented with intriguing symptoms, including extremely high levels of cholesterol in the blood. They often suffered heart attacks at a young age.
Through this rare disease research, the two biochemists, Dr Michael Brown and Dr Joseph Goldstein, discovered cholesterol was regulated through the LDL receptor. The findings earned the researchers a Nobel Prize and formed the basis for the development of one of the world’s most prescribed class of drugs: statins.
Rare disease research leads the way for drug innovation in gene therapy and cell therapies
