INETLLECTUAL PROPERTY PORTFOLIO FOR INVESTIGATION OF THERAPIES FOR TYPE 1 DIABETES

UCSF has amassed an intellectual property portfolio in the area of diabetes research that would provide a company with a proprietary position on several genes and technologies for developing small molecule, cell therapy and/or gene therapy based treatments for diabetes. Our investigators have identified and characterized three human endocrine transcription factors that are required for the differentiation and maintenance of the insulin-producing beta-cells of the pancreas. In addition, for two of these genes they have created knock-out mice which serve as animal models for studying diabetes.

The first factor, neurogenin3 (ngn3), appears to be upstream of all known markers of cells that develop into pancreatic islet cells, which include the insulin-producing beta-cells. Ectopic expression of ngn3 in the gut endoderm of transgenic mouse embryos prior to formation of the pancreas results in a marked increase in the number of islet cells in the pancreatic buds, particularly alpha-cells. Coexpression of ngn3 and a beta-cell specific transcription factor, such as Nkx6.1, may be necessary to specify beta-cells. The regulatory sequences necessary for pancreatic tissue-specific expression of ngn3 have recently been identified.

This second factor, Nkx6.1, is expressed exclusively in the beta-cells of the pancreas. Mice homozygous for a null mutation in Nkx6.1 are characterized by a severe decrease in insulin levels and specifically lack 90-95% of their beta-cells.

The product of the third gene, Nkx2.2, is expressed in three of the islet cell types: alpha, beta, and PP cells. Mice homozygous for a null mutation in Nkx2.2 develop severe hyperglycemia; although immature beta-cells form, there is a complete absence of fully differentiated beta-cells, indicating Nkx2.2 is required for the final differentiation of beta-cells. Its expression also appears to be required for the maintenance of Nkx6.1 expression.

Commercial potential: These three genes and their products may be useful in developing therapies for diabetes and can be used:

• For the development of new beta-cells in vitro or in vivo
• As targets in screens for diabetes therapeutics
• As diagnostic tools for assessing diabetes risk
• For identifying both islet precursor cells and fully differentiated beta-cells

In addition, the regulatory sequences of these genes may be useful for gene therapy approaches involving the targeting of therapeutic genes either to islet precursor cells or to developing beta-cells. The Nkx2.2 and/or Nkx6.1 knockout mice can be used as models for diabetes as well as for assaying cell-based therapeutics or screening therapeutic agents affecting the production of insulin-producing cells.

Intellectual Property:

UCSF has filed patent applications on the human ngn3, Nkx2.2 (issued as U.S. patent No. 6,239,258) and Nkx6.1 genes. Foreign rights are available only for ngn3; the foreign patent application has published through the PCT as WO 059936. We also have an issued U.S. patent 6,127,598 covering the Nkx2.2 and Nkx6.1 knockout mice as well as the use of Nkx2.2 and Nkx6.1 in screens for biologically active agents.

Selected References:

Sander, M. et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. (2000) Development, Vol. 127(24): 5533-40.

Schwitzgebel, V.M. et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. (2000). Development, Vol. 127(16): 3533-42.

Mirmira, R.G. et al. Beta-cell differentiation factor Nkx6.1 contains distinct DNA binding interference and transcriptional repression domains. (2000). J. Biol. Chem., Vol. 275(19): 14743-51.

Sussel, L. et al. Mice lacking the homeodomain transcription factor Nkx 2.2 have diabetes due to arrested differentiation of pancreatic beta cells. (1998). Development, Vol. 125(12): 2213-21.

If you would like to receive further information about this technology and potential licensing opportunities, please contact:

Inquiries to: Karin Immergluck, Ph.D.
(415) 353-4462 phone
(415) 348-1579 fax
karin.immergluck@ucsf.edu

Reference: OTM Case #SF98-010, 99-070