Enobia Pharma Inc.

Universitéde Montreal

Alexion Pharmaceuticals, Inc.

Alexion Pharma Holding

Guy Boileau

Philippe Crine

Isabelle Lemire

Thomas P Loisel

Denis Gravel

Mostafa Hatam

Elaref S Ratemi

Pierre Leonard

Luc Desgroseillers

Robert Heft

Hal Landy

A bone delivery conjugate having a structure selected from the group consisting of: A) X-D-Y-protein-Z; and B) Z-protein-Y-D-X, wherein X is absent or is an amino acid sequence of at least one amino acid; Y is absent or is an amino acid sequence of at least one amino acid; Z is absent or is an amino acid sequence of at least one amino acid; and Dis a poly aspartate wherein n=10 to 16. Compositions comprising same and methods of use thereof.

Bone delivery conjugates and method of using same to target proteins to bone

This invention relates to a soluble form of PHEX, PHEX being a type II integral membrane glycoprotein. This enzyme is the gene product of a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. To produce a soluble form of PHEX, the transmembrane anchor domain has been modified to encode a signal peptidase coding sequence. The soluble PHEX therefore comprises the active ectodomain. An inactive mutant of PHEX is also an object of this invention. Both soluble and inactive mutant forms of PHEX can be used to screen ligands to PHEX. These ligands can also be used as substrates or inhibitors of PHEX. PHEX being phosphaturic, an inhibitor thereof will be used to treat phosphaturia and/or hypophosphatemia. On the opposite, a substrate for PHEX or PHEX itself can be used to treat hyperphosphatemia.

Composition, methods and reagents for the synthesis of a soluble form of human PHEX

The object of the present invention is to increase PHEX activity to improve the osteogenic process in a mammal where this process has been diminished due to pathology or a condition that require osteogenesis. Osteocalcin is an endogenous inhibitor of the PHEX activity. Therefore, the identification of a substance capable of potentiating PHEX activity by preventing the inhibitory action of endogenous inhibitors will improve osteogenesis. Since PHEX is generally associated with the growth plane of bone or teeth and the absence of osteocalcin is associated with increased bone mass, potentiation of PHEX activity can promote bone growth. Increased PHEX activity can also be obtained by administration of the enzyme itself.

Method and compositions for promoting osteogenesis

The present invention relates to derivatives of succinic and glutaric acids and analogues thereof, having the following general formula: 

Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of PHEX

The present invention relates to derivatives of succinic and glutaric acids and analogues thereof, having the following general formula:  useful as inhibitors of PHEX. These derivatives are useful for promoting generation of bone mass and treating or preventing diseases or conditions associated with a phosphate metabolism defect. Methods for preparation and intermediates are also disclosed.

Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of phex

In this paper, we describe RT-PCR strategies that allowed us to identify and clone members of the NEP-like family. Degenerate oligoncleotide primers corresponding to consensus sequences located on either side of the HEXXH consensus sequence for zincins were designed and used in RT-PCR with mouse and human testis cDNAs. DNA fragments with lengths expected from the sequence of this class of enzympes were obtained. These DNA fragments were cloned and sequenced. Using this PCR strategy and the PCR fragments as probes to screen cDNA libraries, three zincin-like peptidases were identified in addition of known members of the family. The cDNA sequences allowed to derive specific probes for Northern and in situ hybridization, and probe human chromosomes to localize the gene and establish potential links to genetic diseases. Furthermore, these cDNA sequences were used to produce recombinant fusion proteins inin order to raise specific antibodies. Finally, the cDNA sequences were cloned in mammalian expression vectors and transfected in various mammalian cell lines to produce active recombinant enzymes suitable for testing specific inhibitors.

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Brossard, Canada

Guy Boileau