APPLICATIONS OF TECHNOLOGY:

• Developing therapies for treating bone related conditions such as osteopenia, osteoporosis, fractures, and sclerosteosis
• Diagnosing and treating Van Buchem’s disease
• Conducting pharmacogenomics of current available osteoporosis treatments such as parathtroid hormone (PTH)
• Studying bone mineral density related diseases using transgenic and knockout animals

ADVANTAGES:

• Enables the development of therapies for bone related diseases for which no effective therapies currently exist
• Provides the possibility of replenishing bone loss in osteoporosis, eliminating hormone replacement therapy and its associated risks
• Provides transgenic and knock-out animals for studying SOST-related bone disease pathways

ABSTRACT:

Gabriela Loots and Edward Rubin at Berkeley Lab have identified regulatory elements that direct the expression of the bone density modulating protein, Sclerostin (SOST).  Of the fifteen identified enhancers, one element in particular is bone-specific and will enable the development of agents that modulate SOST expression, resulting in increased or decreased bone density and representing a novel approach for treating fractures and bone mass density related disorders such as osteoporosis and scleroteosis, as well as diagnosing and treating Van Buchem’s disease.

The researchers have developed transgenic animals that over express SOST from a human BAC as well as one or more of the human SOST enhancer elements in the context of reporter constructs.  These animals will facilitate the discovery of candidate target molecules that regulate SOST expression and further our current understanding of SOST-related disease pathways.  In addition, determining whether SOST is downstream of several bone-formation pathways, and whether increased bone formation is a direct result of SOST downregulation will facilitate pharmacokinetic analysis of drug response in patients suffering from osteoporosis.  Individuals lacking the ability to downregulate SOST in response to PTH or any other anabolic agent would not be responsive to treatments that require SOST downregulation.

Patients with Van Buchem’s disease, a severe sclerosing bone dysplasia, display deletion of a large non-coding region of DNA.  Using BAC recombination and transgenesis, Drs. Loots and Rubin characterized the expression of human sclerostin from normal (SOSTwt) or Van Buchem alleles.  Only the normal SOST allele consistently expressed high levels of human SOST in the adult bone and had an impact on bone metabolism.  These results support the idea that the Van Buchem’s noncoding deletion removes a SOST-specific regulatory element.  Using cross-species sequence comparisons with in vitro and in vivo enhancer assays, the Berkeley Lab researchers were able to identify the fifteen enhancer elements that regulate SOST expression embodied in this invention.

	SOST transgenic expression has a negative impact on bone parameters.  (A) Body weight measurements of 5-month-old male mice – nontransgenic, SOST wildtype, and SOST Van Bruchem deletion. (B) Bone mineral density in the tibia, femur, and lumbar spine shows increased bone mineral density in the mice with down regulated levels of SOST due to deletion of SOST enhancer elements in non-coding regions, characteristic of Van Bruchem disease.

STATUS:

• Published Patent Application. Available for licensing or collaborative research.

FOR MORE INFORMATION:

Loots, G.G., Kneissel, M., Keller H., Baptist M., Chang J., Collette, N.M, Ovcharenko, D., Plajzer-Frick, I., Rubin, E., "Genomic Deletion of a Long-range Bone Enhancer Misregulates Sclerostin in Van Buchem Disease," Genome Research 2005, 15: 928-935.

REFERENCE NUMBER: IB-1944

SEE THESE OTHER BERKELEY LAB TECHNOLOGIES IN THIS FIELD:

• Bioactive Coating Enables Metal Implants to Bond with Bone, IB-1627
• Flexibone: Osteo-mimetic Composites, IB-2104