Guest Column | December 17, 2015

The Impact Of Rare Disease Research On The Development Of New Medicines

The Impact Of Rare Disease Research On The Development Of New Medicines

By Karla Lant, Rare Genomics Institute

When we consider rare disease research and apply a cost-benefit analysis, it becomes clear that the benefits of this kind of research far outweigh the costs. Unfortunately, though, too often this kind of assessment stops short; only the immediate benefits of the research are considered. Discovery of possible cures, treatments, or preventative tools for the diseases in question are generally thought to be the only benefits.

Rare disease research has a much greater effect, however. Although a rare disease affects fewer than 1 in 200,000 people, understanding the molecular and cellular mechanisms underlying rare diseases often provides insight into other diseases — both rare and common. This in turn leads to the development of new medicines.

The Basic Landscape Of Rare Disease Research

In the United States, a “rare” disease is defined as such if it occurs in fewer than one in 200,000 people. However, because there are around 7,000 different rare diseases known so far to the scientific community, this means that about 30 million Americans — 10 percent — are affected by rare disease. To put this in perspective, just over 29 million Americans suffer from diabetes, many of them undiagnosed.

One difference between rare diseases and a disease like diabetes is that rare diseases usually lack any kind of effective treatment options. When treatment options exist, they are typically cost-prohibitive and more likely to remain uncovered by insurance policies. They are often genetic and about half are expressed starting in childhood, meaning sufferers endure their diseases for all their lives (assuming they survive). Rare diseases are often chronic, disabling, progressive, severe, or even fatal.

These sad facts are themselves ample justification to research rare diseases, but there are other important reasons. The study of rare diseases has changed the face of medicine more than most people think. Furthermore, the opportunities to capitalize on what we have learned so far have never been greater. Many experts agree that the study of rare diseases is critical to understanding medicine and biology.

The identification of molecular bases of genetic diseases has progressed significantly since the advent of the Human Genome Project. However, it still takes decades to develop therapeutics. This kind of research fortunately has many applications, making it even more valuable. Furthermore, sometimes existing drugs can be used to treat rare diseases — just as knowledge about rare diseases can help in the fight of more common maladies.

Niemann-Pick Disease And The Ebola Virus

In 2011, teams of Army scientists identified a cellular protein called Niemann-Pick C1 (NPC1). This find was part of a long-term study of Niemann-Pick disease, a rare disease involving an enzyme deficiency that causes organ failure. The team found that NPC1 serves a critical purpose in infection from the Ebola virus, suggesting a defense against this deadly hemorrhagic fever disease.

The importance of finding cures and treatments for — or, better still, defenses against — the Ebola virus is obvious. The disease itself as it naturally occurs holds extremely high value, and given that there is significant concern that Ebola might be used as an agent of biological terrorism, there is even more reason to search.

In two independent studies, researchers confirmed that the Ebola virus requires NPC1 to enter cells. Normal cells contain the NPC1 protein within their membranes; its function is to transport cholesterol inside the cell. Niemann-Pick disease causes an absence of the protein, leading to cells becoming clogged by cholesterol. The eventual result is cellular death. However, the researchers noted that cells that don't make NPC1 cannot be infected by Ebola.

This led one of the teams to discover that mice with NPC1 deficiencies survived lethal doses of Ebola virus. The researchers also successfully inhibited infection by the virus using a compound that blocks NPC1 function. The other team found a novel small molecule that is more than 99 percent effective at blocking the entry of the Ebola virus into the cell; this molecule therefore has the potential to serve in antiviral treatments.

Fanconi Anemia And Cancer Treatment

Fanconi anemia (FA) is a rare genetic disease that is described as a ‘familial infantile pernicious-like anemia’. So far there is no cure for the disease, but over time researchers have made progress with diagnosis and possible treatments. The greatest potential for treatment lies in hematopoietic stem cell transplantation and molecular genetics.

As of 2007 there were twelve causal genes for FA identified. Mutations in two of those, FANCD1/BRCA2 and FANCN/PALB2, have so far been associated with very early childhood cancers. This in turn has led to improved techniques for prenatal diagnosis and clinical management of patients. Researchers have also learned that gene therapy is not always successful.

The global study of FA has produced a much greater understanding of the connections between cancer and genetic instability; this has arisen from the study of chromosomal breaks and repair mechanisms in FA patients. Specifically, researchers have discovered that “FA patients carry a high risk for acute leukemia, squamous cell carcinomas, and other tumors. Young FA patients with certain gene mutations have a higher risk to develop leukemia. The older an FA patient gets, the higher the risk to develop a solid tumor. There are impressive case histories describing adult patients in whom a leukemia or a solid tumor were the first manifestations of FA.”

In other words, there are numerous important connections between the rare disease in question and several manifestations of a common and deadly disease: cancer. Researchers have also learned a great deal about reverse mutations in blood cells, and mosaic FA patients are being studied to discern whether natural gene therapy can benefit patients. Even more importantly, certain FA genes now appear to be ‘caretaker’ genes that play a crucial role in DNA recombination and replication.

Laron Syndrome And Reduction In Pro-Aging Signaling, Cancer, And Diabetes

In 2011, researchers published the results of their longterm study of Laron Syndrome (LS), also called Growth Hormone Receptor Deficiency. The results focused on an isolated Ecuadorian village of people disproportionately affected by the disease — there were 22 people with the disease in the village, while only 250 were known to have the disease worldwide.

Notably, people with LS get neither cancer nor diabetes; researchers wanted to find out why for obvious reasons. They discovered that the disease causes low levels of insulin-like growth factor-1 (IGF-1). The IGF-1 receptor is necessary to the development, growth, and survival of tumors. And since those with LS don’t develop cancer at all, this receptor must be linked to all varieties.

Familial Hemiplegic Migraines And Common Migraines

Much of what we know about the genetic basis for migraines has come from studies focused on a rare disease: familial hemiplegic migraine (FHM). Three genes involved with FHM have been found, and all three encode ion transporters. This suggests this kind of migraine is related to disturbance of neurotransmitter and ion balances in the brain. Scientists now believe that this issue may be a factor in common migraines as well.

Ongoing study of FHM is likely to lead to further insight into not just FHM but other migraines and neurological problems as well. Scientists believe that newer phenotyping techniques and genome-wide association studies are likely to prove very fruitful.

The Case For Funding

Commercial interest in rare diseases is typically limited, stifling private sponsorship of research. Public research funds are needed for research on rare diseases. In fact, the World Health Organization (WHO) identified this need in a background paper associated with its 2004 report, “Priority Medicines for Europe and the World, A Public Health Approach to Innovation.” Rare disease research is valuable for fighting and treating more common diseases. It can also save millions of dollars currently being wasted; our system is slow to properly diagnose rare diseases and therefore sometimes years of needless treatments are administered to patients that don't benefit.

Rare diseases should be assigned a higher priority in public and private research programs. Proposals for rare diseases research should be funded whenever possible and based on this higher priority. Finally, research infrastructure budgets should have room for rare diseases. The benefits go far beyond those affected by the diseases.