Available Technology
New therapeutic targets for the treatment of asthma and COPD
Technology:
Novel EST-derived RNAi screen identifies modulators of beta 2-adrenergic receptor degradation
Markets Addressed
Beta 2-adrenergic receptor (B2AR) agonists are sympathomimetic agents that stimulate bronchodilation. Both short-acting and long-acting B2AR agonists have been used for many years in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Although B2AR undergoes internalization upon binding of its agonists (desensitization), under normal conditions most internalized B2AR is rapidly and efficiently recycled back to the cell surface (resensitization), with very little undergoing lysosomal degradation. However, prolonged stimulation of B2AR leads to receptor ubiquitination and subsequent redirection of internalized B2ARs from recycling to degradation, a process that may limit the efficacy of long term beta 2-agonist treatment.
Innovations and Advantages
Using a novel genome-wide EST-derived shRNA library screen, Harvard University researchers in the laboratory of Professor Quan Lu have identified more than a dozen targets whose inhibition results in reduction of agonist-induced B2AR degradation. To facilitate a FACS-based high-throughput genetic screening strategy, the investigators used a HEK293 cell line that expresses a distally truncated form of human B2AR (293.B2ARt) known to be deficient in its ability to recycle to the surface following agonist-induced internalization. To confirm that the inhibitory effect of the shRNAs on agonist induced B2AR internalization was specifically due to knockdown of genes coded by the shRNAs, synthetic siRNAs against the same candidate target genes, but with different sequences from the shRNAs, were tested in both 293.B2ARt and cells expressing unmodified B2AR (293.B2ARWT).
One of the targets identified is farnesyl diphosphate synthase (FDPS), the pharmaceutical target of the bisphosphonates that are widely used to treat osteoporosis. In 293.B2ARt cells, alendronate induced a dose dependent increase of cell surface B2AR after induction with the agonist isoproterenol. When tested in 293.B2ARWT cells, an increase in cell surface B2AR was seen both before and after agonist induction. These results were further generalized to human primary airway smooth muscle cells, in which inactivation of FDPS was shown to have a similar effect on B2AR surface levels.
These discoveries highlight the possible utility of treating asthma and COPD with a combination of a B2AR agonist and a modulator of agonist-induced B2AR degradation.
Additional Information
Intellectual Property Status: Patent pending.
Publications:
J Nabhan, H Pan, and Q Lu, “Novel EST-derived RNAi screen identifies a critical role for the farnesyl diphosphate synthase in beta 2-adrenergic receptor down-regulation” (in preparation)
J Nabhan, H Pan, and Q Lu, “Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta 2-adrenergic receptor”, EMBO Rep. 2010 Aug;11(8)605-11. Epub 2010 Jun 18. PMID: 20559325
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Inventor(s):
Lu, Quan
Categories:
For further information, please contact:
Debra Peattie, Director of Business Development
(617) 495-3067
Reference Harvard Case #3696