UC San Diego Health Sciences has a stellar reputation for being at the forefront of cutting-edge research and clinical medicine. Frequently the focus is on more prevalent diseases like breast cancer, heart disease, and HIV, which afflict millions of people and attract millions of research dollars. But for the unfortunate few who have rarer diseases (or orphans as the FDA refers to them), there are folks hard-at-work, like Ranjan Dohil, who press forward to find novel solutions to treat orphan diseases like cystinosis and eosinophilic esophagitis.

In his clinical practice, one of the obstacles that Dr. Dohil encounters is patient compliance and tolerability of treatments because of adverse side-effects. Like his counterparts throughout the university, meeting his patients’ needs led him to pursue new approaches.

Dr. Dohil is a pediatric gastroenterologist with an interest in acid-peptic disease. In collaboration with Dr. Jerry Schneider and with support from the Cystinosis Research Foundation, he began a series of small clinical trials which would help to understand possible causes of gastrointestinal symptoms in patients with cystinosis taking cysteamine, pharmacokinetics of cysteamine, and would ultimately lead to the development of a new cysteamine formulation. Dr. Dohil designed a naso-enteric tube that would allow delivery of drug into the stomach, small and large intestine. Data from this study allowed some understanding of how best to develop a new formulation of cysteamine, one that would require fewer daily administrations and would result in fewer symptoms. A preliminary formulation, EC-cysteamine, is currently being studied. Results so far have demonstrated that EC Cysteamine improved gastrointestinal tolerance and absorption. These improvements may lead to optimizing the drug dose thereby lowering the amount of drug needed, lowering the side-effects and increasing patient compliance. In addition, the new formulation may be useful for other metabolic and neurodegenerative diseases.

Cystinosis is a rare genetic disorder that affects over 2,000 people in the United States. While these numbers seem small in comparison to other diseases like cancer, the devastating effects include retinopathy/blindness, kidney failure and a shortened life, if left untreated. The disease symptoms are caused by an accumulation of the amino acid, cystine, in various organs of the body. In 1994, cysteamine – a cystine-depleting agent – was approved to treat cystinosis. Cysteamine can deplete cystinotic cells of more than 90% of their cystine content leading to improved kidney function, especially if diagnosed early. However, a major drawback to cysteamine treatment is the gastrointestinal side-effects of nausea and vomiting. In the literature, the side-effects were colorfully attributed to its ‘repulsive odor and taste’.

A Northern California firm recently acquired the license to Drs. Dohil and Schneider’s cystinosis innovation to advance its march to commercialization. Dr. Dohil will continue as the lead clinical investigator for the ongoing cystinosis clinical trial.

Expanding upon his interest in acid related gastrointestinal disorders in children, Dr. Dohil used a similar approach to developing a treatment for eosinophilic esophagitis (EE), another orphan disease. EE is an inflammatory condition caused by a large number of eosinophils infiltrating the esophagus wall and it affects both adults and children, with an incidence rate of 1 in 10,000 children. Eosinophils are white blood cells or leukocytes that are normally triggered by allergic reactions. The resulting swelling of the esophagus wall causes difficulty in swallowing, vomiting, and overall failure to thrive in children, from lack of nutrition. The cause of EE is unknown, yet many patients have a history of hay fever, food allergy, and asthma. Current treatments include mechanical dilation of the esophagus and oral, topical, or inhalation steroid therapy.

With his colleagues at Children’s Specialist of San Diego, Dr. Dohil began clinical studies for a different treatment for EE. This EE innovation has been licensed by a local San Diego startup company to pursue the compound’s commercial development.

Fortunately for these orphan diseases, they have champions in Dr. Dohil and his colleagues who pursue new treatments for their many patients. The use of the ‘orphan drug’ designation has been critical in helping clinical researchers develop new treatments for rare diseases. In 1983, the Orphan Drug Act was passed by the US Legislature and administered by the Food and Drug Administration to encourage companies to develop treatments for rare diseases. Under this legislation, orphan diseases are defined as diseases affecting fewer than 200,000 people in the United States. Since research and development costs for these orphan drugs can be prohibitively expensive, orphan drug designation allows companies special tax incentives and extended marketing exclusivity.

Since the Orphan Drug Act passed, over 300 orphan drugs and biological products have benefited from this initial designation and brought to market. This group includes: cetuximab (Erbitux®), Velcade®, Bexxar®, Gleevec®, erythropeitin (Epogen®), and rituximab (Rituxan®).

Ranjan Dohil, MD is a clinician-researcher with UC San Diego Medical Center and Rady Children’s Hospital San Diego. He specializes in pediatric gastroenterology, hepatology, and nutrition. Dr. Dohil received his medical degree from the University of Wales College of Medicine, Cardiff, United Kingdom, and continued his training at British Columbia’s Children’s Hospital in Canada. He has been a professor in the School of Medicine, Department of Pediatrics since November 1998.