Pitt Researcher Works to Find Cure for Rare Genetic Disease

By: Cyndy McGrath

A life-like mask sits at the top of Zsolt Urban’s tallest bookshelf.  It bears the likeness of a 12-year-old girl with freckles, big brown eyes, bangs and two, fleshy jowls on either side of her wide grin. The mask is the finished product of a highly precise three-dimensional facial imaging process. For Dr. Urban, this is the face of cutis laxa, a rare disorder of the body’s connective tissue.
“Basically, cutis laxa makes even young people look old because their skin doesn’t have the elasticity it normally would have,” said  Dr. Urban, associate professor of human genetics at the University of Pittsburgh’s Graduate School of Public Health, and head of the only active research program on cutis laxa in the United States.
This weekend, the Urban lab will host patients from across the nation for a cutis laxa clinic and information day. The clinic will allow patients to participate in a range of clinical and research tests, including three-dimensional facial imaging in collaboration with Seth M. Weinberg, Ph.D., of the School of Dental Medicine. The information day will help the patients network and learn more about cutis laxa and associated health conditions.
While the hallmark of cutis laxa is sagging skin, patients very often have other medical conditions, since the disorder affects the connective tissue in other parts of the body, including the heart, lungs, blood vessels and joints.  Some patients may have difficulty breathing because the lung alveoli are not developed. Others may struggle with a variety of cardiovascular problems, including aneurysms, vascular narrowing or stenosis.
Cutis laxa strikes roughly one in a million. There are only an estimated 500 to 1,000 cases in the United States, but those afflicted with the disorder may find a highly frustrating lack of information, understanding and treatment options.
“There’s a huge problem diagnosing these patients,” said Dr. Urban. “Most people have never heard of this condition, including a lot of doctors.  There’s no good test for it, and it may take a long time before patients can get proper care.  We are developing new techniques, such as the three-dimensional facial imaging and skin elasticity testing for accurate and objective diagnosis of our patients. Early diagnosis is essential. A lot of associated health problems are age-dependent and become worse over time.  Conditions like aortic aneurysms can be very risky because there are no signs or symptoms.  Seizures can also be a problem, and they can grow worse over time.”
Researchers world-wide have identified nine genes that can cause the disease in one baffling form or another.  Dr. Urban is responsible for three of those findings and is actively searching for novel genes using the latest DNA sequencing technologies.
“It’s really crucial to identify the genes,” said Dr. Urban. “If you know which gene is mutated, then you can tailor the patient’s care.”
For example, researchers know that one specific type of mutation will affect a patient’s heart and lungs.  Another is characterized by slowed growth and developmental delay.
At the University of Pittsburgh, Dr. Urban and his colleagues look for the origin of the disease. The Pitt researchers examine skin cells collected from cutis laxa patients to determine how they form the extracellular matrix, the proteins that form the meshwork of connective tissue.  At the same time, they are actively searching for a cure. For now, they are using zebra fish, a small freshwater fish with a well-known genome sequence.
“We can easily inactivate the cutis laxa gene in zebra fish,” said Dr. Urban. “We establish models of the disorder in the fish, and then we can search for drugs that will reverse the condition.”
Researchers have found experimental compounds that work on cutis laxa in zebra fish, but much work remains to be done, and Dr. Urban acknowledges that funding is a key component.
His Pittsburgh lab is developing a study of the genetic variation in cutis laxa genes and a patient’s risk for chronic obstructive pulmonary disorder, or COPD.  Lung function is seriously curtailed for patients with the genetic disease, as well as for the millions of Americans currently struggling with COPD.
“Federal funding is slow for the study of rare diseases,” Dr. Urban said.  “As researchers, it’s incumbent upon us to explain how the insights we get from these rare conditions are broadly applicable in other disorders.”