Rare Diseases

According to the Office of Rare Diseases Research at the National Institutes of Health, rare diseases are roughly defined as conditions affecting fewer than 200,000 people in the United States. Although these diseases can be devastating, there is often little incentive for pharmaceutical companies to devote resources to developing new diagnostics and therapeutics for conditions that affect so few people. As a result, rare disease therapeutics are known as “orphan drugs.”

Fortunately, Congress passed the Orphan Drug Act in 1983, providing incentives for researchers and pharmaceutical companies to develop treatments for rare diseases. Since then, more than 200 new drugs and products designed for rare diseases have been developed and made available to patients, a big improvement over the fewer than 10 orphan drugs that reached the market in the decade before 1983. Still, orphan drugs represent a small fraction of the total number of therapeutics developed each year – in 2009 alone, the FDA approved 101 new drugs to treat more common ailments.

SBP research on rare diseases

SBP scientists study the molecular mechanisms underlying several rare diseases:

Congenital Disorders of Glycosylation (CDG)

John Taylor "Rocket" WilliamsJohn Taylor (Rocket) Williams IV suffered from CDG. Dr. Freeze's lab works to discover the causes of CDG and develop new therapies for their treatment.

Children born with Congenital Disorders of Glycosylation (CDG) have inherited mutations in a gene that directs glycosylation – the process by which cells coat proteins with sugars. Lack of sugars disrupts cell growth, differentiation and communication. CDG is actually a group of many diseases, each characterized by a mutation in a different gene. In the past decade, mutations in 25 different genes were identified as causes of CDG. Symptoms of CDG vary widely. Some examples include intellectual disability, digestive problems, seizures and low blood sugar.

With fewer than 1000 patients worldwide, CDG is extremely rare. However, new diagnoses are increasing every year as doctors become more aware of this family of diseases and as scientists identify more genes involved in glycosylation.

In 1996, medical doctors contacted SBP scientists for help in treating Max, a 6-year-old boy diagnosed with CDG. Max was in critical condition due to internal bleeding that his doctors could not stabilize. Since the researchers had already found in the laboratory that glycosylation defects in cells could be reversed by adding a sugar called mannose, they were able to develop a mannose regimen that ultimately stabilized Max's condition. SBP scientists are now working to detect new gene mutations that cause CDG and understand how these defects translate into such a diverse array of symptoms. This research is being used to develop new diagnostic techniques. In addition, SBP scientists are screening a library of molecules to find more therapeutic options for CDG patients.

Enzyme deficiencies of mitochondrial fatty acid oxidation

Enzyme deficiencies of mitochondrial fatty acid oxidation are rare, potentially fatal disorders that affect babies and young children. Children with these diseases cannot tolerate much exercise or go without food for too long because they cannot properly burn fatty acids as a back-up source of energy.

At SBP, scientists are trying to understand the genetic and metabolic mechanisms underlying these diseases. To do this, they are using several mouse models, each of which lacks a different gene encoding an enzyme involved in fatty acid metabolism. These different mouse models demonstrate many of the characteristics of children with these diseases, such as low blood sugar, fat buildup in the liver and sudden death. Researchers hope these mice will continue to provide information about how all these metabolic enzymes work together and help provide molecular clues that doctors could use to better diagnose patients with these diseases. At the same time, information about enzyme deficiencies of mitochondrial fatty acid oxidation is also advancing research on a much more common disease: type 2 diabetes.

Frank-Ter Haar Syndrome (FTHS)

Frank-Ter Haar syndrome (FTHS) is an inherited disorder characterized by abnormalities that affect bones, heart, and eye development. Children born with the disease usually die very young.

FTHS was recently linked to an inherited mutation in a gene that codes for the protein TKS4. Scientists at SBP have been studying TKS4 for its role in the formation of cellular projections known as podosomes, which act as feet that allow for cells to metastasize. Cellular spread is necessary for normal development and wound healing, but can be detrimental when it allows cancer cells spread to other parts of the body. Several SBP scientists recently teamed up to examine a mouse model that lacks TKS4 and shows all the symptoms of FTHS, confirming the hypothesis that TKS4 mutation is responsible for the disease.


Dr. Millan with hypophosphatasia patientDr. Millán with hypophosphatasia patient Morgan Fischer

Hypophosphatasia is an inherited disorder that affects bone mineralization. During normal development, bones and teeth are strengthened by deposits of minerals containing calcium and phosphorus. Patients with hypophosphatasia suffer from weak bones, which can lead to skeletal abnormalities, deformed limbs and other problems. Hypophosphatasia can be relatively mild, affecting only the teeth, or severe and life-threatening.

Scientists at SBP are studying the mechanisms that control the initiation of mineral formation in bone cells. They are also researching enzymes that regulate the concentrations of inorganic pyrophosphate and osteopontin, strong inhibitors of bone mineralization that occur naturally in the body. These translational studies of bone mineralization have helped identify new therapeutic strategies for hypophosphatasia and other disorders using enzyme replacement therapy, small molecule inhibitors and gene therapy.

Multiple Hereditary Exostoses (MHE)

Children with multiple hereditary exostoses (MHE) develop multiple noncancerous bone growths. These abnormal growths, which can number in the hundreds, stunt a child’s normal growth and cause pain and disfigurement. The only treatment for MHE is surgery to remove the growths. If left alone, there is a chance they could become cancerous.

Scientists have long known that people with MHE have inherited a mutated copy of either Ext1 or Ext2, two genes that together encode an enzyme necessary to produce heparan sulfate—a long sugar chain that facilitates cell signals that direct bone cell growth and proliferation. Despite this knowledge, nobody had been able to replicate the disease symptoms in mice, leaving the research community without a tool for studying the underlying cause of MHE or a mechanism for screening new treatments.

By creating a mouse in which the Ext1 gene is deleted in only a few bone cells rather than the entire mouse, SBP scientists were able to successfully mimic MHE. This model provided answers to long-standing questions about the cellular makeup of the bone growths and how they develop. Moreover, researchers gained a tool for screening new drugs that inhibit abnormal bone growth. Other SBP studies of Ext1 and Ext2 are providing new information on the role heparan sulfate plays in development, cancer, inflammation and childhood mental disorders.

For more information

Office of Rare Diseases Research at the National Institutes of Health

Office of Orphan Products Development at the U.S. Food and Drug Administration

The CDG Family Network

The MHE Research Foundation

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