C - Chemistry – Metallurgy – 12 – N
Patent
C - Chemistry, Metallurgy
12
N
C12N 9/00 (2006.01) C07K 14/47 (2006.01) C12N 9/64 (2006.01) A61K 38/00 (2006.01)
Patent
CA 2417873
A novel Asp-ase activity, referred to as BACE secretase/sheddase, has been found to cleave the ectoddomain of BACE after Asp379 (SQDD.dwnarw.) and Asp407 (VVFD.dwnarw.), and likely after Asp451 (PQTD.dwnarw.). The cleavage of BACE by BACE secretase/sheddase renders BACE soluble which in turns appears to enhance the generation of the amyloidogenic peptide A.beta., which has been implicated as a major factor in the etiology of Alzheimer's Disease. The current invention concerns the modulation of this novel BACE secretase/sheddase activity for such applications as the prevention or treatment of a neurodegenerative disorder that is characterized by the generation of A.beta. protein, including Alzheimer's Disease. The invention further comprises a method for the identification of an agent that can alter the ability of BACE secretase/sheddase to associate with and process a known substrate, a method of determining whether an individual is at risk of developing a neurodegenerative disorder that is characterized by the generation of A.beta. protein (such as Alzheimer's Disease) and a kit comprising a vessel or vessels containing BACE secretase/sheddase as well as at least one known substrate of this enzyme, namely, BACE or BACE fragments, or the indirect substrate .beta.APP.
On a découvert qu'une nouvelle activité d'Asp-ase, appelée sécrétase/sheddase BACE, produit le clivage de l'ectodomaine de BACE après Asp¿379? (SQDD.dwnarw.) et Asp¿407? (VVFD.dwnarw.), et de même après Asp¿451? (PQTD.dwnarw.). Le clivage de BACE par sécrétase/sheddase BACE rend le BACE soluble, ce qui à son tour semble améliorer la production du peptide amyloïdogène A.beta., qui est impliqué comme facteur majeur dans l'étiologie de la maladie d'Alzheimer. Cette invention concerne la modulation de cette nouvelle activité de sécrétase/sheddase BACE, pour des applications telles que la prévention ou le traitement d'une affection neurodégénérative qui se caractérise par la production de protéines A.beta., telle que notamment la maladie d'Alzheimer. Cette invention concerne en outre un procédé permettant d'identifier un agent qui peut modifier la capacité de la sécrétase/sheddase BACE de s'associer à un substrat connu et de traiter ce substrat connu, un procédé permettant de déterminer si un individu risque de développer une affection neurodégénérative se caractérisant par la production de protéines A.beta. (telle que la maladie d'Alzheimer) et un kit comprenant un ou des récipients contenant de la sécrétase/sheddase BACE ainsi qu'au moins un substrat connu de cet enzyme tel que BACE ou des fragments de BACE, ou le substrat indirect .beta.APP.
Chretien Michel
Cromlish James A.
Seidah Nabil G.
Goudreau Gage Dubuc
Institut de Recherche Cliniques de Montreal (ircm)
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