Jeffrey Esko, PhD, Professor of Cellular and Molecular Medicine at UC San Diego
Data Enabled by Catalyst Grant Helps Researcher Secure NIH R01 Grant
March 27, 2014 - A knot the size of a golf ball juts from the lower leg, just below the knee. The protuberance is an abnormal bone growth on the tibia. A bone growth on a humerus, seen on an X-ray, resembles a stalk. And alongside a femur, an extra growth curves and extends outward.
These are examples of Multiple Hereditary Exostoses (MHE), a rare, genetic bone disease in which new bone forms on the surface of an existing bone. While predominantly benign, these bone tumors are debilitating, causing chronic pain and deformities that can lead to loss of motion. The disease, also called Hereditary Multiple Exostoses or HME, affects one in every 50,000 people and is the most common genetic disorder affecting bone development. The exostoses usually occur after birth and throughout puberty, and may continue to grow slowly throughout adulthood.
"Multiple Hereditary Exostoses is an autosomal dominant disorder characterized by formation of ectopic cartilage-capped growth – plate-like exostoses next to long bones and other skeletal elements," said Jeffrey Esko, PhD, Professor of Cellular and Molecular Medicine at UC San Diego. "No treatment currently exists, except for surgical removal of the exostoses, orthopedic interventions, and palliative care." Autosomal dominant means a parent with the mutated gene has a 50 percent chance of passing the gene on to a child.
With the help of UC San Diego Clinical and Translational Research Institute (CTRI), Esko took a step closer to discovering a therapy for the disease. His research on MHE is focused on finding small, drug-like agents to alter the metabolism of heparin sulfate (HS), a complex sugar on the surface of cells that affects many factors in bone formation and is believed to be central to the development of normal bones. When there is a mutation in the EXT1 and EXT2 genes, HS becomes less functional, and this underlies the disease, Multiple Hereditary Exostoses.
CTRI awarded Esko a Catalyst Grant last year to support his collaboration with the Conrad Prebys Center for Chemical Genomics (CPCCG). The CPCCG, located at Sanford Burnham Medical Research Institute, a CTRI partner, worked with Esko to convert his prototype assay into an automated, high-throughput system to screen libraries of chemical compounds to identify potential new therapeutic agents. Sanford Burnham's Susanne Heynen-Genel helped adapt Esko's flow-based assay to a high-throughput format that uses confocal fluorescence microscopy for high-resolution optical images. The CTRI funding was to test the feasibility of the plate-based assay and optimize its performance.
"The CTRI grant financed the development of a pilot-scale assay and helped us generate preliminary data," said Esko. The pilot testing analyzed the effects of a small library of compounds on normal cells with HS, as well as cells deficient in HS. Its success provided the foundation for building an assay to screen additional compounds – tens of thousands – in his investigation to identify potential drug candidates to correct the underlying deficiency in MHE patients.
The preliminary results from Esko's screening became part of an R01 application to the National Institutes of Health, which recently awarded him a five-year, $1.8 million R01 grant to continue his research on the disease.
"The (NIH R01) grant would not have been possible without the data generated through the CTRI Drug Discovery Catalyst Grant," said Esko, who is also a member of the Scientific and Medical Advisory Board of the MHE Foundation and the Lubkin Fund for MHE Research, nonprofit organizations that support research and education on MHE. "We continue to work on this project with the hope of one day finding a treatment for this debilitating disease."
Paul J. Mills, co-director of CTRI's Translational Research Technology (TRT) Division, which oversaw the Drug Discovery Catalyst Grant awarded to Dr. Esko, said, "With Catalyst Grant funding, Professor Esko worked with the CPCCG at our partner Sanford Burnham to get the data he needed to support a successful NIH grant proposal, and can now continue his important research to support potential drug discoveries to improve the lives of MHE patients."
Written by Patti Wieser
Find out more about MHE
About UC San Diego Altman Clinical and Translational Research Institute:
UC San Diego Altman Clinical and Translational Research Institute (ACTRI) is part of a national Clinical and Translational Science Award consortium, led by the National Institutes of Health National Center for Advancing Translational Science. Established in 2010, ACTRI provides infrastructure and support for basic, translational and clinical research throughout the San Diego region to bring discoveries from the laboratory to the bedside, and facilitates training and education of the next generation of researchers. ACTRI carries out its activities in collaboration with institutional and corporate partners and currently has more than 1,500 members.